2018 NPA Minisymposium

This minisymposium was originally published in 2018. The information provided in this minisymposium was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this minisymposium.

Lesions of the sellar region are commonly encountered by the surgical pathologist. Approximately 85% of masses from this region are pituitary adenomas, followed in incidence by craniopharyngioma, Rathke cleft cyst, meningioma, and metastasis. Less commonly encountered are spindle cell oncocytoma, granular cell tumor, pituicytoma, and hypophysitis.

Pituitary Adenoma

The diagnosis of pituitary adenoma is usually straightforward on H&E stained sections, which readily identify the monomorphic adenoma cell population. Diagnosis is augmented by reticulin staining, which allows identification of loss of normal pituitary acinar architecture. Reticulin also aids in identification of adjacent normal anterior gland where it highlights the maintained acinar architecture.

In the 2017 World Health Organization Classification of Tumours of Endocrine Organs, pituitary adenomas remain classified by hormone expression as assessed by IHC staining. Antibodies directed against the specific hormones (growth hormone [GH], prolactin [PRL], thyroid stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], follicle stimulating hormone [FSH], and luteinizing hormone [LH]) can usually adequately subclassify a pituitary adenoma. However, classification based upon the driving transcription factor for each adenoma subtype is emerging as an additional method for classification. Antibodies directed against the transcription factors steroidogenic factor 1 (SF1) and transcription factor 1 (Pit-1) are becoming useful diagnostic tools. SF1 drives gonadotroph adenomas while Pit-1 drives GH, PRL, and TSH adenomas. A third transcription factor, pituitary cell-restricted T box factor (Tpit), drives corticotroph adenomas but its antibody is not yet commercially available as an IHC marker. Table 1 summarizes the transcription factors associated with each of the pituitary adenoma subtypes.

Why should the pathologist subtype pituitary adenomas? In some cases, hormonal subtype can dictate therapy. In prolactinomas, for instance, endocrinologists can utilize dopamine agonists to treat any residual adenoma that might persist after resection. Additionally, certain subtypes of adenoma have been shown to be more clinically aggressive in that they tend to be more invasive, have earlier recurrence, and are more resistant to treatment. The following adenoma subtypes are recognized as having a more aggressive behavior:

  • Acidophil stem cell adenoma
  • Crooke cell adenoma
  • Lactotroph adenoma when occurring in men
  • Pit-1 positive plurihormonal adenoma
  • Sparsely granulated somatotroph adenoma
  • Silent corticotroph adenoma

Pit-1 Adenomas

Adenomas driven by the transcription factor Pit-1 include lactotroph, somatotroph, mixed somato-lactotroph, mammosomatotroph, acidophil stem cell, and thyrotroph adenomas. The former “silent type 3 adenoma” is now reclassified as Pit-1 positive plurihormonal adenoma. For the purpose of this review, only the more common lactotroph and somatotroph adenomas will be addressed. Lactotroph adenoma (prolactinoma) typically exhibits strong cytoplasmic prolactin immunoreactivity. Prolactinomas can also occasionally exhibit psammomatous calcifications and amyloid derived from prolactin. In cases where the patient comes to surgery after long-term dopamine agonist therapy, stromal fibrosis and cytoplasmic shrinkage causing the cells to resemble lymphocytes may be evident. Somatotroph (GH) adenomas are nearly equally divided into densely and sparsely granulated types. Sparsely granulated GH adenomas show weak and focal GH staining, while densely granulated GH adenomas show strong and diffuse GH staining.

SF1 Adenomas

Adenomas driven by the transcription factor SF1, which are exclusively of the gonadotroph type, are a common subtype encountered by the surgical pathologist. Traditionally, gonadotroph adenomas have been defined by positive immunostaining for LH and/or FSH, with or without alpha-subunit (α-SU) staining. However, even when these hormonal stains are negative, positive staining for SF1 alone is sufficient to diagnose gonadotroph adenoma. The majority of previously classified “null cell” adenomas – negative for all hormonal markers – are now recognized as SF1-driven and therefore would be classified as gonadotroph adenomas.

Tpit Adenomas

Adenomas driven by the transcription factor Tpit include densely granulated corticotroph adenomas, sparsely granulated corticotroph adenomas, and Crooke cell adenomas. Corticotroph adenomas are usually microadenomas (<1 cm) and declare themselves clinically even when they are very small and somewhat inconspicuous radiologically and grossly. Consequently, it is not uncommon for the surgical pathologist to be asked to provide an intraoperative frozen section consultation to determine whether a miniscule corticotroph adenoma has been removed. When a corticotroph adenoma is functional, adjacent normal pituitary cells can undergo so-called Crooke cell change, wherein cells exhibit ring-like cytoplasmic accumulation of cytokeratin filaments. Low-molecular-weight cytokeratin IHC can be used to highlight these accumulations. An uncommon, aggressive ACTH-immunoreactive variant is the Crooke cell adenoma, wherein the neoplastic cells themselves exhibit Crooke cell change.

Table 1: Pituitary adenoma subtypes based on transcription factor classification.

Transcription FactorAdenoma Subtype
Pituitary transcription factor 1 (Pit-1)Lactotroph (densely and sparsely granulated)
Somatotroph (densely and sparsely granulated)
Mixed somato-lactotroph
Acidophil stem cell
Pit-1 positive plurihormonal
Steroidogenic factor 1 (SF1)Gonadotroph
Pituitary cell-restricted T box factor (Tpit)Corticotroph (densely and sparsely granulated)
Crooke cell adenoma
Undetermined lineage

Null cell

Atypical Adenoma and Carcinoma

The term “atypical pituitary adenoma” is no longer utilized in the WHO 2017 classification. Since a MIB1 proliferative index above 3% may portend increased risk of early recurrence, it is often recommended that this index be included in the surgical pathology report. However, the use of p53 IHC is no longer recommended as a prognostic tool. Pituitary carcinoma, a rare entity, can only be diagnosed in the setting of clinicoradiologic evidence of metastasis. Invasion of surrounding structures, such as the cavernous sinus, is not a criterion for the diagnosis of pituitary carcinoma.


Two histologically distinct types of craniopharyngioma are described: adamantinomatous and papillary. Recent molecular studies have shown that the adamantinomatous type is driven by β-catenin (CTNNB1) mutations, while the papillary type is driven by the BRAF V600E mutations. Adamantinomatous craniopharyngioma (by far the more common of the two types) is characterized by large, plump cuboidal squamous cells that are associated with anuclear keratin material known as “wet keratin.” Large collections of keratin may demonstrate calcification and ossification. This type of tumor also exhibits a superficial palisading layer of cells often associated with a middle layer of stellate cells. A foreign body giant cell reaction may be seen along with cholesterol clefts and/or xanthomatous change. The irregular margins of the tumor may exhibit piloid gliosis with Rosenthal fibers; therefore, biopsies of tumors may be confused with pilocytic astrocytoma. The papillary variant, found mainly in adults, is usually suprasellar in location but can also be seen in the third ventricle. It exhibits a solid growth pattern with the “papillary” configurations resulting from separation of squamous epithelial sheets. This variant lacks the presence of wet keratin or calcification, and may additionally be distinguished by demonstrating BRAF V600E immunoreactivity.

Rathke Cleft Cyst

Rathke cleft cysts are derived from remnants of the primitive Rathke cleft. Typically arising in the sella turcica, they may also present as suprasellar tumors where they can be associated with visual field deficits. Histologically, the cysts are lined by ciliated respiratory epithelium with scattered goblet cells and are frequently associated with focal squamous metaplasia. The cyst lining is generally immunoreactive for cytokeratins 8 and 20, further distinguishing it from craniopharyngioma.

The TTF1-Associated Family of Sellar Tumors

Pituicytoma, granular cell tumor, and spindle cell oncocytoma exhibit overlapping histologic features and share IHC expression of thyroid transcription factor-1 (TTF1), suggesting a common lineage. Among these tumors, pituicytoma has the greatest propensity to occur as a purely intrasellar tumor while the others tend to be either suprasellar or mixed intrasellar and suprasellar. Classified as a WHO grade I tumor, the pituicytoma grows slowly and is usually treated by surgery alone. Histologically, pituicytoma is composed of solid sheets of elongate, bipolar spindle cells arranged in either a fascicular or storiform pattern. Pituicytoma is usually strongly immunoreactive for S100, but variably immunoreactive for GFAP and EMA. Granular cell tumor is strongly and diffusely CD68 immunoreactive, indicative of a dense lysosomal content. Bridging the histologic features between pituicytoma and granular cell tumor is the spindle cell oncocytoma, a tumor that is distinctive for its dense cytoplasmic contents by electron microscopy. Hypothesized to originate from the folliculostellate cells that surround adenohypophyseal acini, spindle cell oncocytoma exhibits strong immunoreactivity for S100 and EMA.


Since inflammatory masses of the anterior and/or posterior pituitary mimic adenomas on neuroimaging, the task of diagnosis usually falls solely to the pathologist. Subtypes of primary hypophysitis can overlap and include lymphocytic, xanthomatous, granulomatous, plasma-cell rich, IgG4-related, and necrotizing variants. Secondary hypophysitis has been associated with Crohn disease, Whipple disease, granulomatosis with polyangiitis (Wegener granulomatosis), and ipilimumab therapy.

Take Home Points

  • The majority of sellar region neoplasms are pituitary adenomas.
  • Although the 2017 WHO Classification of Tumours of Endocrine Organs continues to subtype pituitary adenomas based upon hormonal IHC subtyping, classification by transcription factor IHC is emerging as a useful adjunct.
  • Craniopharyngioma is subclassified into two histologic types: adamantinomatous and papillary. The former is driven by β-catenin (CTNNB1) mutations and the latter by BRAF V600E mutations.
  • TTF1-associated pituitary tumors include pituicytoma, granular cell tumor, and spindle cell oncocytoma.
  • There are many subtypes of primary hypophysitis that can overlap histologically.


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