Practical Pituitary Pathology
What Does the Pathologist Need to Know?
Sylvia L. Asa, MD, PhD
● Context.—The sellar region is the site of frequent pa- Conclusions.—The initial examination requires routine
thology. The pituitary is affected by a large number of path- hematoxylin-eosin to establish whether the lesion is a pri-
ologic entities arising from the gland itself and from adja- mary adenohypophysial proliferation or one of the many
cent anatomical structures including brain, blood vessels, other types of pathology that occur in this area. The most
nerves, and meninges. The surgical pathology of this area common lesions resected surgically are pituitary adeno-
requires the accurate characterization of primary adeno- mas. These are evaluated with a number of special stains
hypophysial tumors, craniopharyngiomas, neurologic neo- and immunohistochemical markers that are now available
plasms, germ cell tumors, hematologic malignancies, and
metastases as well as nonneoplastic lesions such as cysts, to accurately classify these tumors. The complex subclas-
hyperplasias, and inﬂammatory disorders. siﬁcation of pituitary adenomas is now recognized to re-
Objective.—To provide a practical approach to the di- ﬂect speciﬁc clinical features and genetic alterations that
agnosis of pituitary specimens. predict targeted therapies for patients with pituitary dis-
Data Sources.—Literature review and primary material orders.
from the University of Toronto. (Arch Pathol Lab Med. 2008;132:1231–1240)
A number of pathologic processes occur in the region of
the pituitary gland. They include primary pituitary
lesions that are unique to this site, as well as disorders
ment of new pharmacotherapeutic agents, improved min-
imally invasive surgical approaches, and targeted radio-
therapeutic techniques. The surgical pathologist must
arising in adjacent anatomical structures such as brain, therefore recognize the important role of morphologic
blood vessels, nerves, and meninges. The surgical pathol- analysis in classifying sellar pathology for the diagnosis
ogy of this area requires the accurate characterization of and management of the pituitary patient.
neoplastic lesions, including pituitary adenoma and car-
cinoma, craniopharyngioma, neurologic neoplasms, germ THE ROLE OF CLINICAL INFORMATION
cell tumors, and hematologic malignancies, and their dis- The importance of clinical information cannot be over-
tinction from nonneoplastic disorders such as cysts, hy- emphasized in this ﬁeld. Patients with pituitary disease
perplasias, and inﬂammatory lesions.1,2 The spectrum of may present with symptoms and signs of hormone excess,
pituitary pathologies that represent the surgical pathology or they may manifest features of a mass lesion, including
of the pituitary is outlined in Table 1. headache, visual impairment, and hypopituitarism. The
The commonest disorder is the pituitary adenoma, a le- former usually indicates a primary adenohypophysial dis-
sion that is increasingly recognized as a highly prevalent order, but it should be recognized that hyperprolactinemia
ﬁnding. A recent meta-analysis has shown that the post- may be a nonspeciﬁc ﬁnding because of a mass lesion that
mortem prevalence of pituitary adenoma is 14.4% and that obstructs the pituitary stalk, interrupting blood ﬂow that
radiologic studies identify a lesion consistent with pitui- maintains prolactin (PRL) under tonic inhibition. The lat-
tary adenoma in 22.2% of the population, providing an ter can be the result of any mass lesion in the region of
overall estimated prevalence of 16.9%.3 Although many of the sella. The ﬁnding of diabetes insipidus or cranial nerve
these lesions are considered to be incidental ﬁndings, dysfunction make the diagnosis of a primary adenohy-
many have unrecognized impact on fertility, longevity, pophysial cell proliferation unlikely and instead suggest
and quality of life, and their clinical signiﬁcance is increas- other tumor types or inﬂammatory disorders.
ingly gaining attention. Moreover, the management of Despite the importance of clinicopathologic correlation,
these lesions has seen major changes with the develop- the reality is that many pathologists are faced with diag-
nosing a lesion without clinical information. In most in-
stances it is possible to determine a remarkable amount
Accepted for publication January 30, 2008. of information with careful morphologic evaluation using
From the Department of Pathology, University Health Network, To- a targeted approach.
The author has no relevant ﬁnancial interest in the products or com- AT THE TIME OF SURGERY
panies described in this article.
Reprints: Sylvia L. Asa, MD, PhD, Department of Pathology, Univer- The initial handling of tissue obtained at pituitary sur-
sity Health Network, 200 Elizabeth St, 11th Floor, Toronto, Ontario, gery should ensure adequate ﬁxation in formalin for his-
Canada M5G 2C4 (e-mail: firstname.lastname@example.org). tology and immunohistochemistry. In rare cases, there
Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa 1231
Table 1. Classiﬁcation of Pituitary Pathology* gland intact. In the case of a large lesion, the sella may be
eroded to the point where it must be resected en bloc.
However, in most patients the sellar diaphragm can be
Benign† opened and the dorsum sellae fractured to push it pos-
Pituitary adenoma teriorly, allowing the gland to be removed intact. The
gland then can be evaluated grossly and sectioned for
Granular cell tumor complete histologic evaluation.
Meningioma There are 2 approaches to the sectioning and embed-
Schwannoma ding of the pituitary (Figure 1). Many investigators use
Chordoma sagittal sections through the gland; others prefer trans-
Vascular and mesenchymal tumors verse sections. The former permit examination of the stalk;
Malignant the latter provide a more thorough examination of the
Pituitary carcinoma gland and more accurate determination of the geographic
Gliomas distribution of the various cell types, at the expense of
Germ cell tumor examining the stalk carefully.
Lymphoma/leukemia/Langerhans cell histiocytosis
Vascular and mesenchymal tumors HISTOLOGY
Miscellaneous (salivary gland lesions, melanoma, etc) The initial evaluation of a pituitary specimen involves
Nonneoplastic review of material stained with hematoxylin-eosin. This
routine stain allows the distinction of primary adenohy-
pophysial pathologies from other entities. Rathke cleft
Inﬂammatory lesions cysts, arachnoid cysts, and dermoid cysts (Figure 2) are
Infectious recognized based on preoperative clinical and radiologic
ﬁndings and conﬁrmed with the identiﬁcation of the ap-
Cysts propriate cyst lining.4 Hypophysitis of any type5 can be
Rathke cleft cysts readily recognized with this conventional stain (Figure 3).
Arachnoid The various tumors that arise in the sella—gliomas, me-
ningiomas, schwannomas, and chordomas—are consid-
Aneurysms ered based on this analysis and their workup is different
Meningoencephalocele than that of a pituitary adenoma. Unusual hypothalamic
Brown tumor of bone neuronal gangliocytomas and gangliogliomas can give
rise to clinical features of hormone excess that can mimic
* Surgical pathology only, not including developmental and meta-
bolic lesions that are not biopsied. pituitary adenoma,6 but must be recognized, either dis-
† Although classiﬁed as benign, many of these lesions are locally tinct from an adenoma or associated with one.
invasive and cause signiﬁcant morbidity and mortality. Craniopharyngioma is a unique tumor of the sellar re-
gion that is derived from the oropharyngeal remnants of
Rathke pouch. These lesions have a characteristic mor-
may be a need for ultrastructural analysis; because this phology that requires only routine hematoxylin-eosin
situation is not often predicted clinically, it is recommend- staining for identiﬁcation and classiﬁcation (Figure 4).
ed that a small piece of tissue be routinely ﬁxed for elec- They are composed of cords or islands of squamoid epi-
tron microscopy and retained in the event that it is need- thelial cells in a loose ﬁbrous stroma with varying degrees
ed. Currently there is no need for special handling of tis- of desquamation and intervening cysts that often contain
sue for other diagnostic techniques. a thick oily ﬂuid.1 They can be subclassiﬁed as adaman-
Most pituitary specimens are very small and the tissue tinomatous and papillary types; the former are known to
may be compromised by freezing artifact when surgeons harbor mutations of the -catenin gene as a speciﬁc mo-
request intraoperative consultation and frozen sections are lecular pathogenetic mechanism.7,8 These lesions have a
performed. In some centers, pathologists use smear tech- bimodal distribution with peaks in childhood and in the
nology for intraoperative consultation to prevent this ar- sixth decade. Although adamantinomatous lesions pre-
tifact; this method uses less tissue but requires experience dominate in childhood, most craniopharyngiomas in
for interpretation. Sometimes, the only diagnostic tissue is adults have a mixed pattern and the clinical signiﬁcance
in the material used for the intraoperative procedure and of subclassiﬁcation remains uncertain.
it is fraught with artefact that precludes accurate evalua- Germ cell tumors of the sella resemble germ cell tumors
tion. Because valid indication for intraoperative consulta- in other sites of the body.9 Hematologic malignancies of
tion is rare, this procedure should be restricted for use the sella are usually systemic disorders but occasionally
only when the clinical situation is unusual or when the arise as primary plasmacytomas or lymphomas.10–12
surgeon encounters unexpected ﬁndings and the intra- Metastatic malignancies are common in the pituitary,13,14
operative diagnosis might change the surgical approach. usually at a late stage of disseminated malignancy when
the clinical diagnosis is known. However, occasionally
THE AUTOPSY PITUITARY these lesions are detected early, and particularly in pa-
The high prevalence of pituitary adenomas means that tients with no known history of a primary malignancy,
pathologists will often identify these lesions as incidental they can be clinically challenging. The lesions that most
ﬁndings in autopsies. The main concern is handling of the frequently give rise to pituitary metastasis are breast,
material for analysis. It is recommended that the sella tur- lung, and prostate carcinomas. The metastatic tumor usu-
cica be examined after the brain is removed; the hypo- ally involves the neurohypophysis and extrasellar struc-
physial stalk should be cut as high as possible to leave the tures, creating a clinical presentation of diabetes insipidus
1232 Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa
Figure 1. a, There are 2 approaches to the sectioning and embedding of the autopsy pituitary, shown from a superior view on the left with the
anterior lobe (AL) down, the posterior lobe (PL) up, and the stalk pointing out of the plane of the picture. Sagittal sections (S) allow examination
of the stalk but require multiple sections through each lobe to identify the various cell types. b, A transverse section (T) provides a full section of
the gland that allows more accurate determination of the geographic distribution of the various cell types in the anterior lobe (AL) and identiﬁcation
of basophil invasion of the intermediate lobe corticotrophs (arrow) into the posterior lobe (PL). The somatotrophs are mainly located in the lateral
wings (GH), lactotrophs in the posterolateral wings (PRL), and corticotrophs in the median wedge (ACTH). Thyrotrophs are scattered with some
concentration in the anterior median wedge and gonadotrophs are found throughout the parenchyma (periodic acid–Schiff, original magniﬁcation
and nerve palsies that is not consistent with pituitary ad- when induced by excess hypophysiotropic hormones. Ex-
enoma.15,16 The common lesions are readily diagnosed on amples of the latter include cases of primary target organ
routine histopathology, but a metastatic well-differentiated failure, such as primary hypothyroidism,18,19 or hormone
neuroendocrine carcinoma (Figure 5) can be a diagnostic excess produced by neoplasms, such as hypothalamic gan-
dilemma.15,17 The expression of speciﬁc markers, such as gliocytomas or ectopic sources of growth hormone–releas-
thyroid transcription factor 1, CDX-2, or peptides of gut ing hormone or corticotrophin-releasing hormone, such as
or lung origin, may be required to distinguish these le- bronchial, gastroenteropancreatic, adrenal, or prostatic en-
sions from a primary pituitary neoplasm. docrine tumors.20 Hyperplasia may be clinically indistin-
guishable from adenoma, usually in patients with acro-
PRIMARY ADENOHYPOPHYSIAL CELL megaly or Cushing disease. Radiologic imaging some-
PROLIFERATIONS times identiﬁes differences; in hyperplasia, the prolifera-
Once a pituitary lesion is determined to be composed tion is diffuse and there is no normal rim that enhances
of epithelial cells with neuroendocrine differentiation and with gadolinium.21 However, this subtle difference is often
thought to be of primary pituitary origin, the classiﬁcation overlooked and it falls to the pathologist to make the di-
of the lesion will require several steps. First, the lesion agnosis. In this regard, the reticulin stain is a very useful
must be identiﬁed as hyperplasia or neoplasia. Second, the tool. Normal adenohypophysis is composed of small acini
cell population responsible for the proliferation must be of pituitary cells surrounded by an intact reticulin net-
established. Finally, in the case of a neoplasm, the behav- work (Figure 6, a). In hyperplasia, the acinar architecture
ior, prognosis, and potential therapy of choice must be is maintained and the reticulin network is preserved, but
determined. the acini are increased in size (Figure 6, b). In contrast,
pituitary adenomas are characterized by complete disrup-
ADENOMA OR HYPERPLASIA? tion of the reticulin ﬁber network (Figure 6, c). Immuno-
Hyperplasia is controlled cell proliferation that is in- histochemical stains are required to determine the hyper-
duced by a stimulus and stops when the stimulus is re- plastic cell population, and these stains will identify the
moved. Pituitary hyperplasia can be physiologic, as when admixed normal cells that contain all of the normal ade-
lactotrophs proliferate during pregnancy, or pathologic nohypophysial hormones.1
Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa 1233
Figure 2. Pituitary Rathke cleft cyst. These cystic lesions are lined by ciliated columnar to cuboidal epithelium with occasional goblet cells. The
cyst is usually collapsed at the time of surgery and the lining is found adherent to adenohypophysial parenchyma (hematoxylin-eosin, original
Figure 3. Lymphocytic hypophysitis. The adenohypophysis is inﬁltrated by chronic inﬂammatory cells including lymphocytes and plasma cells.
The few residual parenchymal cells are oncocytic (hematoxylin-eosin, original magniﬁcation 200).
Figure 4. Craniopharyngioma. This papillary craniopharyngioma is composed of abundant squamous epithelium in a loose ﬁbrous stroma with
focal inﬂammation (hematoxylin-eosin, original magniﬁcation 100).
Figure 5. Metastatic neuroendocrine carcinoma. This metastasis from a primary endocrine carcinoma of lung mimics a pituitary adenoma in
architecture and cytology. Both lesions can be positive for synaptophysin and chromogranin; therefore, other markers are required to establish the
diagnosis. Strong nuclear positivity for thyroid transcription factor 1 (not shown) conﬁrmed the diagnosis (hematoxylin-eosin, original magniﬁcation
PITUITARY ADENOMA CLASSIFICATION The pituitary is composed of at least 6 distinct cell
Clinically pituitary adenomas are classiﬁed as hormon- types. Each cell is responsible for the production and se-
ally active functioning adenomas and nonfunctioning ad- cretion of at least 1 hormone. Recent advances in molec-
enomas that often present with visual impairment and hy- ular biology have clariﬁed 3 major pathways of cytodif-
popituitarism. Approximately two thirds of clinically di- ferentiation of adenohypophyseal cells (Figure 7) that are
agnosed lesions are functioning adenomas. determined by a complex pattern of transcription factor
Pituitary adenomas are also classiﬁed based on size and expression.22,23 These transcription factors can help in clas-
invasiveness. Microadenomas are deﬁned as less than 1 sifying adenomas.24–28
cm; macroadenomas are larger than 1 cm. Large tumors Corticotrophs differentiate ﬁrst in the human fetal pi-
growing upward are deﬁned as showing suprasellar ex- tuitary and the expression of the proopiomelanocortin
tension. Tumors are also classiﬁed radiologically and by (POMC) gene is regulated by the Tpit transcription factor29
the neurosurgeon as invasive or not, based on their inﬁl- that mediates its action in concert with Ptx1 and
tration into surrounding structures (dura, bone, sinuses, neuroD1,30,31 which were previously identiﬁed as cortico-
etc). troph upstream transcription element-binding proteins.
1234 Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa
Figure 6. Reticulin staining in normal, hyperplastic, and neoplastic pituitary. The normal gland (a) has an intact reticulin pattern identifying acini.
Hyperplasia (b) has intact but expanded acini. In contrast, an adenoma (c) has total breakdown of acinar architecture (Gordon-Sweet silver stain,
original magniﬁcations 100).
The second line of differentiation temporally in the human whose hormone production is dependent on steroidogenic
gland is determined by Pit-1, a protein that activates the factor 1 and GATA-2 in the presence of estrogen recep-
growth hormone (GH), PRL, and -thyrotropin ( -thy- tor.28,40
roid–stimulating hormone [TSH]) genes.32–37 Pit-1 initiates Each cell type can give rise to tumors that are clinically
GH expression and somatotroph differentiation. Expres- functioning or silent. Some tumor types have morphologic
sion of estrogen receptor allows the expression of PRL and variants based on patterns of immunoreactivity for hor-
GH a bihormonal population of mammosomatotrophs.38 mones and subcellular structures and, in occasional cases,
The development of mature lactotrophs is dependent on ultrastructural features1,2; the variants are thought to re-
the presence of a putative GH repressor that has yet to be ﬂect differing pathogenetic mechanisms and may predict
identiﬁed. Some of the Pit-1–expressing cells further ex- differing responses to therapy. The current clinicopatho-
press thyrotroph embryonic factor39 and develop into thy- logic classiﬁcation of pituitary adenomas is shown in Table
rotrophs in the presence of a GH repressor and GATA-2.40 2 and the detailed morphologic subclassiﬁcation is out-
In physiologic states, somatotrophs, mammosomato- lined in Table 3.
trophs, and lactotrophs transdifferentiate in what is
thought to be a reversible fashion.41 It has been shown in The Pathology of Hormone Excess Syndromes
animal models that somatotrophs can also transdifferen- Most patients with Cushing disease have small lesions
tiate into thyrotrophs in severe hypothyroidism and this that are difﬁcult to localize by magnetic resonance imag-
too is thought to be reversible.42 These changes indicate ing. The differential diagnosis is pituitary adenoma versus
ﬂuidity of 4 cell types that are all dependent on Pit-1. The corticotroph hyperplasia. The former is far more common,
third line of cytodifferentiation is that of the gonadotrophs but the distinction is important and requires the use of
Figure 7. Pathways of cell differentiation in
the adenohypophysis. The 3 main pathways
of cell differentiation are determined by tran-
scription factors that can serve as diagnostic
markers. Pit-1 indicates pituitary transcription
factor 1; SF-1, steroidogenic factor 1; ER, es-
trogen receptor; TEF, thyrotroph embryonic
factor; and GH, growth hormone.
Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa 1235
Table 2. Clinicopathologic Classiﬁcation of Pituitary Adenomas*
Clinically Functioning Adenomas Clinically Silent Adenomas
Adenomas causing GH excess
Somatotroph adenomas Silent somatotroph adenomas
Adenomas causing hyperprolactinemia
Lactotroph adenomas Silent lactotroph adenomas
Lactotroph adenomas with GH reactivity
Adenomas causing TSH excess
Thyrotroph adenomas Silent thyrotroph adenomas
Adenomas causing ACTH excess
Corticotroph adenomas Silent corticotroph adenomas
Adenomas causing gonadotropin excess
Gonadotroph adenomas Silent gonadotroph adenomas
Plurihormonal adenomas Hormone negative adenomas
* GH indicates growth hormone; TSH, thyroid-stimulating hormone (thyrotropin); and ACTH, adrenocorticotropic hormone.
reticulin staining and adrenocorticotropic hormone (Figure 8). This change is seen in patients with pituitary
(ACTH) immunohistochemistry. The classical microade- corticotroph adenoma, ectopic ACTH secretion, primary
noma is a densely granulated adenoma composed of adrenal pathology, or iatrogenic administration of gluco-
strongly basophilic cells. These adenomas exhibit strong corticoids. When this change is present but no tumor is
positivity with the periodic acid–Schiff stain. Immunohis- seen, the pathologist must search for a microadenoma that
tochemically, they demonstrate expression of ACTH and may be only 1 to 2 mm and multiple sections through the
generally have very strong reactivity with the CAM 5.2 specimen may be required to ﬁnd the lesion. In the ab-
antibody to keratins 7 and 8. sence of an identiﬁed adenoma, the pathologist can only
The pathologist should also examine the nontumorous issue a report that indicates the presence of Crooke hya-
gland to determine if there is Crooke hyaline change, a line, consistent with Cushing syndrome, and the outcome
morphologic marker of feedback suppression that is usu- of surgery alone will indicate the true nature of this dis-
ally found in nontumorous corticotrophs and conﬁrms order. Because very small microadenomas can be lost dur-
that the patient has elevated circulating glucocorticoids ing surgery, perhaps suctioned during aspiration of blood
Table 3. Immunohistochemical Classiﬁcation of Pituitary Adenomas*
Tumor Transcription Factor Hormone(s) CAM 5.2
Adenomas containing GH Pit-1
Somatotroph adenomas GH
Densely granulated somatotroph adenomas -Subunit Perinuclear
Sparsely granulated somatotroph adenomas Fibrous bodies
Mammosomatotroph adenomas GH, PRL, -subunit
Mixed somatotroph-lactotroph adenomas
Plurihormonal GH-producing adenomas GH, PRL, -subunit, -TSH
Adenomas containing PRL Pit-1, ER
Lactotroph adenomas PRL
Sparsely granulated lactotroph adenomas PRL (Golgi pattern)
Densely granulated lactotroph adenomas PRL (diffuse)
Acidophil stem cell adenomas PRL, GH Fibrous bodies
Adenomas containing TSH Pit-1, TEF, GATA-2
Thyrotroph adenomas -Subunit, -TSH
Adenomas containing ACTH Tpit
Densely granulated corticotroph adenomas ACTH
Sparsely granulated corticotroph adenomas ACTH
Crooke cell adenoma ACTH Dense bands
Adenomas containing gonadotropins SF-1, ER, GATA-2
Gonadotroph adenomas -Subunit, -FSH, -LH
Plurihormonal adenomas ? Multiple
Silent subtype 3 adenomas Multiple
Unusual plurihormonal adenomas Multiple
Hormone-negative adenomas None
Null cell adenomas None
* GH indicates growth hormone; Pit-1, pituitary transcription factor 1; PRL, prolactin; TSH, thyroid-stimulating hormone (thyrotropin); TEF,
thyrotroph embryonic factor; ACTH, adrenocorticotropic hormone; SF-1, steroidogenic factor 1; ER, estrogen receptor; FSH, follicle-stimulating
hormone; and LH, luteinizing hormone.
1236 Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa
of growth hormone–releasing hormone by endocrine tu-
mors as described previously. Reticulin is a critical stain
to exclude this possibility and ensure appropriate man-
agement for these patients.
Growth hormone–secreting adenomas may be mono-
hormonal somatotroph adenomas, bihormonal mammo-
somatotroph adenomas, or plurihormonal adenomas of
the Pit-1 family that also make TSH. Monohormonal so-
matotroph adenomas can be densely granulated or sparse-
ly granulated. The distinctions can impact medical thera-
py in the event of surgical therapy45,46; therefore, accurate
classiﬁcation is important. Indeed, it appears that the most
important distinction is between densely and sparsely
granulated types, because the pathophysiology of these
lesions will determine their response to the current ther-
apies that are available: somatostatin analogues versus
GH-antagonists and possibly dopamine agonists.47
All of these adenomas exhibit nuclear Pit-1 reactivity
and variable cytoplasmic GH positivity. Mammosomato-
Figure 8. Crooke hyaline change. Nontumorous corticotrophs in the trophs stain for PRL as well, and the unusual plurihor-
pituitary of a patient with elevated glucocorticoids exhibit accumula- monal adenomas contain -TSH. All of the densely gran-
tion of hyaline material in the cytoplasm; the hyaline traps large lyso- ulated variants are acidophilic and also contain -subunit.
somes known as ‘‘enigmatic bodies’’ that are found in corticotrophs.
The periodic acid-Schiff–positive hormonal content is sequestered at
The sparsely granulated somatotroph adenoma is the most
the periphery and in the juxtanuclear region of the cell (original mag- difﬁcult to diagnose, because it is often either negative or
niﬁcation 400). only weakly positive for GH. Indeed the most critical im-
munostain in this setting is the CAM 5.2 keratin stain. It
identiﬁes perinuclear keratin in densely granulated ade-
in the operative ﬁeld, an operative success can be assumed nomas, including mammosomatotrophs and plurihormon-
if biochemical normality is achieved along with regression al lesions (Figure 9, a). In contrast, it clearly decorates ﬁ-
of clinical signs and symptoms. In contrast, a surgical fail- brous bodies in the sparsely granulated adenomas (Figure
ure will require more careful clinical evaluation of the pa- 9, b). These ﬁbrous bodies can often be recognized with-
tient to exclude an ectopic source of ACTH or ACTH-like out the keratin stain. The tumor cells often have bilobed
peptide, primary adrenal disease, or a missed pituitary or concave, pleomorphic nuclei that are distorted by pale
lesion elsewhere in the gland. homogenous eosinophilic globules.
In a patient in whom no tumor is found and there is no The patient presenting with hyperprolactinemia usually
Crooke hyaline change of nontumorous corticotrophs, the is treated with medical therapy. Patients who come to sur-
diagnosis becomes complex. One possibility is that the pa- gery either have failed medical therapy or suffer signiﬁ-
tient has corticotroph hyperplasia; this diagnosis requires cant adverse effects induced by all of the dopaminergic
a careful evaluation of reticulin and corticotroph distri- agonists now available. Because most lactotroph adenomas
bution that can be very difﬁcult.43,44 Another possibility is respond well to these drugs with hormone normalization
pseudo-Cushing, a signiﬁcant medical pitfall that can oc- and tumor shrinkage, it is important for the pathologist
casionally result in unnecessary pituitary surgery. to exclude the many other causes of hyperprolactinemia,
Generally, larger lesions tend to be obvious adenomas including hypophysitis and all of the various nonadeno-
but not obviously basophilic adenomas, because they are hypophysial neoplasms identiﬁed previously.
usually sparsely granulated, chromophobic adenomas. Lactotroph adenomas are subclassiﬁed into sparsely
The presence of periodic acid–Schiff positivity and weak granulated and densely granulated variants. Sparsely
ACTH reactivity makes the diagnosis evident, but these granulated adenomas are usually highly responsive to do-
stains can also be equivocal in this setting. The addition pamine agonists and therefore usually exhibit major
of Tpit is very helpful. changes because of the previous therapy. Only untreated
Crooke cell adenoma is a rare variant of corticotroph adenomas of this type exhibit the usually chromophobic
adenoma. In this unusual lesion, the adenomatous cells morphology with abundant cytoplasm and characteristic
exhibit the features of suppressed corticotrophs. These tu- juxtanuclear PRL immunoreactivity (Figure 10). More
mors are often associated with atypical clinical histories, commonly, the lesions are composed of small cells in a
and the diagnosis may be unclear, or there may be a his- ﬁbrous stroma, resembling inﬂammation, plasmacytoma,
tory of cyclical Cushing syndrome. The morphology of or lymphoma. The diagnosis is conﬁrmed by the identi-
these lesions is quite atypical, with prominent nuclear ﬁcation of strong nuclear positivity for Pit-1; usually they
pleomorphism and large cells that can resemble ganglio- have at least focal PRL positivity. The rare densely gran-
cytoma or metastatic carcinoma. Periodic acid–Schiff pos- ulated lactotroph adenomas are composed of acidophilic
itivity and immunoreactivity for ACTH as well as the cells with strong and diffuse cytoplasmic positivity for
dense ring of keratin that ﬁlls the tumor cell cytoplasm PRL. Another unusual pituitary adenoma causing hyper-
and is identiﬁed with CAM 5.2 deﬁne this rare entity. prolactinemia is the so-called acidophil stem cell adeno-
When the patient is known to have acromegaly or gi- ma, an oncocytic lesion characterized by Pit-1 nuclear
gantism, the diagnosis of a GH-secreting adenoma is al- staining, variable PRL and GH reactivity, and ﬁbrous bod-
most certain. However, rarely these patients can have so- ies identiﬁed with the CAM 5.2 immunostain.
matotroph hyperplasia resulting from ectopic production The presentation of a patient with TSH excess requires
Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa 1237
Figure 9. Keratin patterns in somatotroph adenomas. Densely granulated somatotroph and mammosomatotroph adenomas exhibit a perinuclear
pattern of keratin (a) identiﬁed with the CAM 5.2 antibody. In contrast, sparsely granulated somatotroph adenomas have a unique pattern of staining
that identiﬁes globular ‘‘ﬁbrous bodies’’ (b) with this same antibody (original magniﬁcations 200).
Figure 10. Prolactin staining in sparsely granulated lactotroph adenoma. This tumor is usually treated medically, but when untreated it exhibits
a highly speciﬁc staining pattern for prolactin that is localized to the Golgi complex (prolactin immunohistochemistry, original magniﬁcation
Figure 11. Gonadotroph adenoma. Most clinically nonfunctioning adenomas are of gonadotroph differentiation. They often have areas of solid
architecture, but their characteristic feature is the formation of trabeculae of elongated cells with distinct polarity that form pseudorosettes around
vascular channels (hematoxylin-eosin, original magniﬁcation 400).
the exclusion of thyrotroph hyperplasia (see ‘‘Adenoma or troph differentiation. They have a highly characteristic his-
Hyperplasia?’’). The rare thyrotroph adenomas are usu- tologic pattern, in which solid sheets, nests, and even si-
ally highly inﬁltrative macroadenomas with stromal ﬁbro- nusoidal patterns are interrupted by pseudopapillae and
sis and marked nuclear atypia. Immunohistochemically, striking pseudorosettes around vascular channels (Figure
thyrotroph adenomas express -subunit and -TSH. 11). They usually are composed of admixtures of 2 cell
types: tall columnar cells line pseudopapillae and rosettes,
Clinically Nonfunctioning Adenomas and polygonal cells comprise the bulk of the lesion. On-
The diagnosis of a clinically nonfunctioning adenoma cocytic change can be observed in all patterns. Gonado-
requires appropriate classiﬁcation for prognostication. The troph adenomas express -subunit, -follicle–stimulating
majority of these lesions are gonadotroph adenomas; these hormone, and -luteinizing hormone in scattered patterns
very rarely present with clinical or biochemical evidence and to variable degrees; they also express steroidogenic
of hormone excess. Nevertheless, they produce follicle- factor 1 with strong nuclear reactivity.
stimulating hormone and/or luteinizing hormone and Occasional clinically silent adenomas are positive for
they express the transcription factors that prove gonado- Pit-1 and GH, PRL, or -TSH; these lesions should be clas-
1238 Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa
siﬁed as adenomas of the appropriate type as indicated amination. If this is impractical, certainly specimens from
previously, with the additional qualiﬁcation of ‘‘silent’’ ad- patients with atypical histories deserve this type of han-
enoma. Silent corticotroph adenomas are thought to arise dling, because they will be the cases most likely to require
from cells that fail to process the ACTH precursor, pro- this ancillary study.
opiomelanocortin, into the biologically active 1-39 ACTH.
These lesions manifest Tpit and ACTH immunoreactivity Prognosis
and they are strongly positive for keratins 7 and 8. Indeed Prognostication remains a major challenge in pituitary
they resemble functioning corticotroph adenomas of the 2 pathology. Proliferative activity51–53 using markers such as
types, sparsely and densely granulated variants; however, proliferating cell nuclear antigen, Ki-67/MIB-1, and anti-
they are invariably macroadenomas and there is no asso- apoptotic Bcl-2 have unfortunately demonstrated no con-
ciated Crooke hyaline in nontumorous corticotrophs. sistent correlation with tumor invasiveness or recurrence.52
These lesions are generally much more aggressive than Although invasive pituitary adenomas and carcinomas ex-
other silent adenomas, and recurrence is extremely com- hibit a high DNA topoisomerase II index, this indicator
mon. The pathophysiology of the lack of clinical symptom- has no signiﬁcant advantage over MIB-1 as a prognostic
atology of other silent adenomas is not known. marker.54 Cyclooxygenase 2 expression correlates with pa-
As immunohistochemical markers become more sophis- tient age, but not with tumor size or invasiveness.55 De-
ticated, the number of truly unclassiﬁed adenomas is fall- tection of telomerase expression may predict recurrence in
ing. The rare tumor that is completely negative for all hor- pituitary adenomas.56 Galectin-3, a -galactoside–binding
mones and transcription factors is classiﬁed as a ‘‘null cell protein implicated in cellular differentiation and prolifer-
adenoma.’’ These usually behave like gonadotroph ade- ation as well as angiogenesis, tumor progression, and me-
nomas. tastasis, may play a role in pituitary tumor progression.57
Unfortunately, none of these is a true marker of biologic
The Question of Plurihormonality behavior. The best predictive marker remains the tumor
Reports of various combinations of hormones in unusu- classiﬁcation based on hormone content and cell structure.
al plurihormonal pituitary adenomas were extremely com- For example, among acromegalics who fail surgical resec-
mon in the past. However, the application of highly spe- tion, response to long-acting somatostatin analogues is
ciﬁc monoclonal antibodies and the understanding of cell best predicted by the subtype of somatotroph adenoma as
differentiation have clariﬁed many of the controversies. densely or sparsely granulated.45,46 This ﬁnding renders
Reports of adenomas expressing GH or PRL with gonad- the value of a CAM 5.2 keratin stain more important than
otropins are now recognized to reﬂect nonspeciﬁc cross- almost any other immunostain in this setting. A silent cor-
reactivity.48 The fact that cells of the Pit-1 lineage express ticotroph adenoma will recur more often and more ag-
-subunit and that many antisera raised against follicle- gressively than a silent gonadotroph adenoma. A silent
stimulating hormone or luteinizing hormone recognized subtype 3 adenoma will almost certainly behave invasi-
-subunit explains many of these anomalies. The use of vely, inﬁltrating the base of the skull, whereas a silent ad-
high-quality monoclonal antisera has made the occurrence enoma of the gonadotroph lineage will usually grow by
of unusual plurihormonal proﬁles exceptionally rare. In- expansion upward.
deed, some of these lesions represent double adenomas or Pituitary carcinoma, by deﬁnition a lesion that exhibits
‘‘collision’’ tumors.49 Most lesions respect the lines of dif- distant cerebrospinal and/or systemic metastasis, is an ex-
ferentiation attributable to the 3 transcription factor line- ceptionally rare lesion that cannot be deﬁned by morpho-
ages. Even the rare silent subtype 3 adenoma is usually logic parameters of the primary tumor.
positive for Pit-1, PRL, GH, and -TSH with other reac- CONCLUSION
tivities likely reﬂecting -subunit cross-reactivity. This le-
sion is characterized by intense stromal ﬁbrosis and high The approach to pituitary pathology is complex and re-
vascularity. Other distinct features are identiﬁed by elec- quires recognition of many pathologic entities. Familiarity
tron microscopy. with inﬂammatory and neurologic diseases must be cou-
pled with a detailed understanding of pituitary hyperpla-
The Role of Electron Microscopy sia and adenoma classiﬁcation. In the past, a diagnosis of
The classiﬁcation of pituitary adenomas is based on ‘‘adenoma’’ was considered sufﬁcient for many patients,
careful studies that used immunohistochemistry, electron but the advances in pituitary medicine demand a more
microscopy, and immunoelectron microscopy to identify thorough clinicopathologic diagnosis that will guide pa-
structure-function correlations.50 Many of the ultrastruc- tient management.
tural features that were recognized as characterizing spe- References
ciﬁc tumor types are now identiﬁed by immunohisto- 1. Asa SL. Tumors of the Pituitary Gland. Washington, DC: Armed Forces In-
stitute of Pathology; 1998. Atlas of Tumor Pathology ; 3rd series, fascicle 22.
chemistry. For example, ﬁbrous bodies were considered 2. DeLellis RA, Lloyd RV, Heitz PU, Eng C. Tumours of Endocrine Organs.
the hallmark of the sparsely granulated somatotroph ad- Lyon, France: IARC Press; 2004. World Health Organization Classiﬁcation of Tu-
enoma, and these are now readily identiﬁed with the mours.
3. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas:
CAM 5.2 immunostain. a systematic review. Cancer. 2004;101:613–619.
There remain situations in which the histology and im- 4. Shin JL, Asa SL, Woodhouse LJ, Smyth HS, Ezzat S. Cystic lesions of the
munohistochemical proﬁle are atypical and these cases re- pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke’s
cleft cyst, and arachnoid cyst. J Clin Endocrinol Metab. 1999;84:3972–3982.
quire electron microscopy for accurate classiﬁcation. The 5. Cheung CC, Ezzat S, Smyth HS, Asa SL. The spectrum and signiﬁcance of
best approach to the use of this diagnostic tool is to ﬁx primary hypophysitis. J Clin Endocrinol Metab. 2001;86:1048–1053.
and embed a small fragment of all pituitary tumors at the 6. Puchner MJA, Ludecke DK, Saeger W, Riedel M, Asa SL. Gangliocytomas
time of receipt in the event that electron microscopy may of the sellar region—a review. Exper Clin Endocrinol. 1995;103:129–149.
7. Sarubi JC, Bei H, Adams EF, et al. Clonal composition of human adaman-
be required, recognizing that only a small number of spec- tinomatous craniopharyngiomas and somatic mutation analyses of the patched
imens will ever require sectioning and ultrastructural ex- (PTCH), Gs and Gi2 genes. Neurosci Lett. 2001;310(1):5–8.
Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa 1239
8. Sekine S, Shibata T, Kokubu A, et al. Craniopharyngiomas of adamantino- protein, Pit-1, activates both growth hormone and prolactin promoters transcrip-
matous type harbor -Catenin gene mutations. Am J Pathol. 2002;161:1997– tionally. Genes Dev. 1989;3:946–958.
2001. 34. Li S, Crenshaw EB III, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld
9. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural MG. Dwarf locus mutants lacking three pituitary cell types result from mutations
history and pathogenesis. J Neurosurg. 1985;63:155–167. in the POU-domain gene pit-1. Nature. 1990;347:528–533.
10. Samaratunga H, Perry-Keene D, Apel RL. Primary lymphoma of the pitu- 35. Ingraham HA, Albert VR, Chen R, et al. A family of POU-domain and
itary gland: a neoplasm of acquired MALT? Endocr Pathol. 1997;8:335–341. Pit-1 tissue-speciﬁc transcription factors in pituitary and neuroendocrine devel-
11. Kuhn D, Buchfelder M, Brabletz T, Paulus W. Intrasellar malignant lym- opment. Annu Rev Physiol. 1990;52:773–791.
phoma developing within pituitary adenoma. Acta Neuropathol (Berl). 1999;97: 36. Rosenfeld MG. POU-domain transcription factors: pou-er-ful developmen-
311–316. tal regulators. Genes Dev. 1991;5:897–907.
12. Landman RE, Wardlaw SL, McConnell RJ, Khandji AG, Bruce JN, Freda 37. Yan G, Pan WT, Bancroft C. Thyrotropin-releasing hormone action on the
PU. Pituitary lymphoma presenting as fever of unknown origin. J Clin Endocrinol prolactin promotor is mediated by the POU protein Pit-1. Mol Endocrinol. 1991;
Metab. 2001;86:1470–1476. 5:535–541.
13. Roessmann U, Kaufman B, Friede RL. Metastatic lesions in the sella turcica 38. Day RN, Koike S, Sakai M, Muramatsu M, Maurer RA. Both Pit-1 and the
and pituitary gland. Cancer. 1970;25:478–480. estrogen receptor are required for estrogen responsiveness of the rat prolactin
14. Kovacs K. Metastatic cancer of the pituitary gland. Oncology. 1973;27: gene. Mol Endocrinol. 1990;4:1964–1971.
533–542. 39. Drolet DW, Scully KM, Simmons DM, et al. TEF, a transcription factor
15. McCormick PC, Post KD, Kandji AD, Hays AP. Metastatic carcinoma to expressed speciﬁcally in the anterior pituitary during embryogenesis, deﬁnes a
the pituitary gland. Br J Neurosurg. 1989;3:71–79. new class of leucine zipper proteins. Genes Dev. 1991;5:1739–1753.
16. Fassett DR, Couldwell WT. Metastases to the pituitary gland. Neurosurg 40. Scully KM, Rosenfeld MG. Pituitary development: regulatory codes in
Focus. 2004;16(4):E8. mammalian organogenesis. Science. 2002;295:2231–2235.
17. Branch CL Jr, Laws ER Jr. Metastatic tumors of the sella turcica masquer- 41. Frawley LS, Boockfor FR. Mammosomatotropes: presence and functions in
ading as primary pituitary tumors. J Clin Endocrinol Metab. 1987;65:469–474. normal and neoplastic pituitary tissue. Endocr Rev. 1991;12:337–355.
18. Khalil A, Kovacs K, Sima AAF, Burrow GN, Horvath E. Pituitary thyrotroph 42. Horvath E, Lloyd RV, Kovacs K. Propylthiouracil-induced hypothyroidism
hyperplasia mimicking prolactin-secreting adenoma. J Endocrinol Invest. 1984;7: results in reversible transdifferentiation of somatotrophs into thyroidectomy cells:
399–404. a morphologic study of the rat pituitary including immunoelectron microscopy.
19. Kubota T, Hayashi M, Kabuto M, et al. Corticotroph cell hyperplasia in a Lab Invest. 1990;63:511–520.
patient with Addison disease: case report. Surg Neurol. 1992;37:441–447. 43. Trouillas J, Guigard MP, Fonlupt P, Souchier C, Girod C. Mapping of cor-
20. Sano T, Asa SL, Kovacs K. Growth hormone-releasing hormone-producing ticotropic cells in the normal human pituitary. J Histochem Cytochem. 1996;44:
tumors: clinical, biochemical, and morphological manifestations. Endocr Rev. 473–479.
1988;9:357–373. 44. McNicol AM. Patterns of corticotropic cells in the adult human pituitary
21. Ezzat S, Asa SL, Stefaneanu L, et al. Somatotroph hyperplasia without pi- in Cushing’s disease. Diag Histopathol. 1981;4:335–341.
tuitary adenoma associated with a long standing growth hormone-releasing hor- 45. Ezzat S, Kontogeorgos G, Redelmeier DA, Horvath E, Harris AG, Kovacs
mone-producing bronchial carcinoid. J Clin Endocrinol Metab. 1994;78:555– K. In vivo responsiveness of morphological variants of growth hormone-producing
560. pituitary adenomas to octreotide. Eur J Endocrinol. 1995;133:686–690.
22. Asa SL, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas. 46. Bhayana S, Booth GL, Asa SL, Kovacs K, Ezzat S. The implication of so-
Endocr Rev. 1998;19:798–827. matotroph adenoma phenotype to somatostatin analog responsiveness in acro-
23. Asa SL, Ezzat S. Molecular basis of pituitary development and cytogenesis. megaly. J Clin Endocrinol. Metab. 2005;90:6290–6295.
Front Horm Res. 2004;32:1–19. 47. Asa SL, DiGiovanni R, Jiang J, et al. A growth hormone receptor mutation
24. Asa SL, Puy LA, Lew AM, Sundmark VC, Elsholtz HP. Cell type-speciﬁc impairs growth hormone autofeedback signaling in pituitary tumors. Cancer Res.
expression of the pituitary transcription activator Pit-1 in the human pituitary and 2007;67:7505–7511.
pituitary adenomas. J Clin Endocrinol Metab. 1993;77:1275–1280. 48. Labat-Moleur F, Trouillas J, Seret-Begue D, Kujas M, Delisle M-B, Ronin
25. Friend KE, Chiou Y-K, Laws ER Jr, Lopes MBS, Shupnik MA. Pit-1 messenger C. Evaluation of 29 monoclonal and polyclonal antibodies used in the diagnosis
ribonucleic acid is differentially expressed in human pituitary adenomas. J Clin of pituitary adenomas: a collaborative study from pathologists of the Club Francais ¸
Endocrinol Metab. 1993;77:1281–1286. de l’Hypophyse. Pathol Res Pract. 1991;187:534–538.
26. Friend KE, Chiou YK, Lopes MBS, Laws ER Jr, Hughes KM, Shupnik MA. 49. Jastania RA, Alsaad KO, Al Shraim M, Kovacs K, Asa SL. Double adenomas
Estrogen receptor expression in human pituitary: correlation with immunohisto- of the pituitary: transcription factors Pit-1, T-pit, and SF-1 identify cytogenesis and
chemistry in normal tissue, and immunohistochemistry and morphology in mac- differentiation. Endocr Pathol. 2005;16:187–194.
roadenomas. J Clin Endocrinol Metab. 1994;78:1497–1504. 50. Kovacs K, Horvath E. Tumors of the Pituitary Gland. Washington, DC:
27. Zafar M, Ezzat S, Ramyar L, Pan N, Smyth HS, Asa SL. Cell-speciﬁc ex- Armed Forces Institute of Pathology; 1986. Atlas of Tumor Pathology; 2nd series,
pression of estrogen receptor in the human pituitary and its adenomas. J Clin fascicle 21.
Endocrinol Metab. 1995;80:3621–3627. 51. Knosp E, Kitz K, Perneczky A. Proliferation activity in pituitary adenomas:
28. Asa SL, Bamberger A-M, Cao B, Wong M, Parker KL, Ezzat S. The tran- measurement by monoclonal antibody Ki-67. Neurosurgery. 1989;25:927–930.
scription activator steroidogenic factor-1 is preferentially expressed in the human 52. Amar AP, Hinton DR, Krieger MD, Weiss MH. Invasive pituitary adenomas:
pituitary gonadotroph. J Clin Endocrinol Metab. 1996;81:2165–2170. signiﬁcance of proliferation parameters. Pituitary. 1999;2(2):117–122.
29. Lamolet B, Pulichino AM, Lamonerie T, et al. A pituitary cell-restricted T 53. Thapar K, Kovacs K, Scheithauer BW, et al. Proliferative activity and in-
box factor, Tpit, activates POMC transcription in cooperation with Pitx homeo- vasiveness among pituitary adenomas and carcinomas: an analysis using the
proteins. Cell. 2001;104:849–859. MIB-1 antibody. Neurosurgery. 1996;38:99–107.
30. Lamonerie T, Tremblay JJ, Lanctot C, Therrien M, Gauthier Y, Drouin J. Ptx1, 54. Vidal S, Kovacs K, Horvath E, et al. Topoisomerase IIalpha expression in
a bicoid-related homeo box transcription factor involved in transcription of the pituitary adenomas and carcinomas: relationship to tumor behavior. Mod Pathol.
pro-opiomelanocortin gene. Genes Dev. 1996;10:1284–1295. 2002;15:1205–1212.
31. Poulin G, Turgeon B, Drouin J. NeuroD1/beta2 contributes to cell-speciﬁc 55. Vidal S, Kovacs K, Bell D, Horvath E, Scheithauer BW, Lloyd RV. Cyclo-
transcription of the proopiomelanocortin gene. Mol Cell Biol. 1997;17:6673– oxygenase-2 expression in human pituitary tumors. Cancer. 2003;97:2814–2821.
6682. 56. Yoshino A, Katayama Y, Fukushima T, et al. Telomerase activity in pituitary
32. Ingraham HA, Chen R, Mangalam HJ, et al. A tissue-speciﬁc transcription adenomas: signiﬁcance of telomerase expression in predicting pituitary adenoma
factor containing a homeodomain speciﬁes a pituitary phenotype. Cell. 1988;55: recurrence. J Neurooncol. 2003;63:155–162.
519–529. 57. Riss D, Jin L, Qian X, et al. Differential expression of galectin-3 in pituitary
33. Mangalam HJ, Albert VR, Ingraham HA, et al. A pituitary POU domain tumors. Cancer Res. 2003;63:2251–2255.
1240 Arch Pathol Lab Med—Vol 132, August 2008 Pituitary Pathology—Asa