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 Table of Contents  
PRACTICE CHANGING CONTINUING EDUCATION - CLINICS IN ENDOCRINE HISTOPATHOLOGY
Year : 2018  |  Volume : 4  |  Issue : 4  |  Page : 240-250

Pituitary tumors: Changing paradigms in understanding, nomenclature and the newer basis of classification


Department of Pathology, Institute of Human Behaviour and Allied Sciences, Delhi, India

Date of Web Publication29-Oct-2018

Correspondence Address:
Sujata Chaturvedi
Department of Pathology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi - 110 095
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/astrocyte.astrocyte_43_18

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  Abstract 

The pituitary gland is embryologically divided into two main lobes: adenohypophysis (anterior) and neurohypophysis (posterior). Last five decades have witnessed changes in the tumor classifications – anterior pituitary in 2017 and posterior in 2016, based on hormonal immunohistochemistry, molecular profiles, and pituitary specific transcription factors. Few newer entities/terms have been added and at the same time certain terms have been modified/discarded. In this article, relevant anatomy, development, histology, incidence, and clinical manifestations of pituitary tumors evolution of various classification systems and recommended current classification of pituitary tumors; the genetic alterations and the diagnostic implications for today's pathologist have been reviewed in a comprehensive manner.

Keywords: Adenohypophysis, immunohistochemistry, neurohypophysis, pituitary gland, transcription factors


How to cite this article:
Tiwari S, Pant I, Chaturvedi S. Pituitary tumors: Changing paradigms in understanding, nomenclature and the newer basis of classification. Astrocyte 2018;4:240-50

How to cite this URL:
Tiwari S, Pant I, Chaturvedi S. Pituitary tumors: Changing paradigms in understanding, nomenclature and the newer basis of classification. Astrocyte [serial online] 2018 [cited 2019 Jan 24];4:240-50. Available from: http://www.astrocyte.in/text.asp?2018/4/4/240/244296


  Introduction Top


The pituitary gland, a pea-sized organ seated on the sella turcica is called the master organ not without any reason. Any abnormal growth or malfunctioning can wreak havoc on the entire body. Structurally, the pituitary is composed of (i) anterior pituitary or adenohypophysis which constitutes about 80% of the gland, involved in hormone production and controlled by the hypothalamus and (ii) posterior pituitary or neurohypophysis which consists of pituicytes, the modified glial cells, and axonal processes derived from the hypothalamus. The WHO “blue books” have traditionally included lesions of the adenohypophysis in WHO Classification of Tumors of Endocrine Organs and those of the neurohypophysis under WHO Classification of Tumors of the Central Nervous System.

In this article, the relevant anatomy of pituitary gland, its development and histology, incidence, and clinical manifestations of pituitary tumors; evolution of various classification systems and recommended current classification of pituitary tumors and the genetic alterations and the diagnostic implications for today's pathologist have been reviewed in a comprehensive manner.


  Anatomy and Development of Pituitary Gland Top


Pituitary gland is composed of two separate lobes developing from two completely different parts: one is from invagination of roof of oral ectoderm (which is Rathke's pouch), in response to extrinsic and neural epithelial signals[1],[2] known as anterior lobe or adenohypophysis. Adenohypophysis, itself, is composed of three distinct parts, pars tuberalis (surrounds infundibular stalk), pars distalis (where hormone secreting cells are present), and pars intermedia (little significance in humans). Six specialized cells of adenohypophysis secrete hormones: the lactotrophs (prolactin), somatotrophs (growth hormone), thyrotrophs (thyroid stimulating hormone), corticotrophs (adrenocorticotrophic hormone, ACTH), gonadotrophs (follicular-stimulating hormone and luteinizing hormone), and mammosomatotrophs (growth hormone and prolactin).

The downgrowth of neuroectoderm (nervous tissue) from hypothalamus gives rise to posterior lobe or neurohypophysis, which is composed of neuroglial cells and nerve fibers from hypothalamus. Posterior lobe secretes two hormones vasopressin or antidiuretic hormone (ADH) and oxytocin synthesized by paraventricular nucleus and supraoptic nucleus of hypothalamus, respectively.

Activation of extrinsic signaling pathways[3],[4],[5] as well as homeobox transcription factors (TF) encoding genes are mandatory for evolution of pituitary gland. Timely activation and inhibition as well as temporal and spatial organized expression of these TFs lead to its development and determine cell-specific lineages for hormone production.[6] In response to extrinsic and intrinsic signals, the ectodermal primordium cells (derived from anteriormost, midline portion of embryo contiguous with anterior neural ridge) proliferate and differentiate in a distinct spatial and temporal fashion. Extrinsic signals include SHH (sonic hedgehog), FGFR (fibroblast growth factor receptor), WNT (wingless type), Retinoids, etc. Oral ectoderm thickens in response to SHH, which is expressed in whole of this epithelium excluding the part which forms Ratkhe's pouch.[8] The epithelium continues proliferating in response to neural epithelial signals and with new expression of BMP4 (bone morphogenic protein 4).[4] Around embryonic age day 6, the invagination of oral ectoderm happens in response to SOX 3 (SRY-related HMG-box 3) and restricted expression of Hesx1 (HESX – homeobox 1, its expression starts rostrally and progresses distally) transcription factor followed by expression of BMP 4 (bone morphogenetic protein) and NKX 2 (NK2 – homeobox 1), forming the basic structure of pituitary gland.[10] At the same time, precursor cells migrate into the pouch followed by their differentiation and proliferation by activation of Lhx 3 and Lhx 4 TFs, respectively.[11] Finally, ventral-dorsal gradient of BMP2 (bone morphogenic protein 2) and fibroblast growth factor 8 (FGF 8) is established by synchronous action of these TFs with Pitx1 and Pitx2. The ventral most TFs get activated that include GATA2 (member of GATA family of zinc-finger transcriptional regulatory proteins), ISl1, αSU (α subunit) along with simultaneous inhibition of expression of ACTH, and PIT-1 (pituitary specific POU- class homeodomain transcription factor).[12] The most dorsal cells experience higher levels of FGF8 signaling, so these accordingly express Pitx1, TPIT (T- box family member, TBX 19), NeuroD1 (neurogenic differentiation 1), and LIF (leukemia inhibitory factor). GATA2, which inhibits expression of PIT1 in the cells, differentiates cells into gonadotrophs and thyrotrophs. For thyrotrophs, PIT1 is essential and, in cells destined to develop into thyrotrophs, GATA2 expression is below the threshold required to block PIT1 activation.[12] The intermediate cells get differentiated into PIT1 positive lactotrophs, somatotrophs, and PIT1- and GATA-positive thyrotrophs. The dorsal TFs activate TPIT, from which cells get differentiated into corticotrophs [Figure 1].[6],[8]
Figure 1: Development of Pituitary Gland. SHH = Sonic HedgeHog, PIT-1 = Pituitary-Specific POU-Class Homeodomain Transcription Factor, ERα = Estrogen Receptor α, GATA-2 = Member of GATA Family of Zinc-Finger Transcriptional Regulatory Proteins, T-PIT = T-Box Family Member TBX 19, SF-1 = Steroidogenic Factor 1, α SU = α Subunit, Neuro D1 = Neurogenic Differentiation 1, LIF = Leukemia Inhibitory Factor, TEF = Thyrotroph Embryonic Factor.

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As can be made out, a complex interplay of transcription factors is involved in the development of pituitary gland. Functions of key TFs are summarized in [Table 1], whereas histology of pituitary gland is described in [Table 2].[21]
Table 1: Transcription Factors Involved in Development of Pituitary Gland and Their Functions

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Table 2: Histology of Pituitary Gland

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  Incidence, Clinical Features, and Histopathology of Pituitary Tumors Top


Pituitary tumors constitute almost 15% of central nervous system tumors.[22] Pituitary adenoma or neuroendocrine tumors itself constitute 10% of all CNS tumors. Mostly, pituitary adenomas (65%) are functional (clinical hormone producing) and remaining 35% are nonfunctional (without clinically apparent hormone production).[23]

Overwhelming tumors of sellar region masses are pituitary adenomas (85%), followed by craniopharyngiomas (3%), Rathke cleft cysts (2%), meningiomas (1%), and metastases (0.5%). Hypophysitis, pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis are less in frequency.[24] Clinical features and histopathology of pituitary tumors are detailed in [Table 3].[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36]
Table 3: Clinical Features and Histopathology of Pituitary Tumors

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  Evolution of Various Classification Systems Top


As the intricacies of pituitary development became known and therapeutic options became more objective, the classification system of pituitary tumors also evolved. In 1979, Hardy introduced a classification [Table 4]A based on maximum tumor size and sella disruption,[37] and in 1993, Knosp gave a clinical classification of pituitary tumors on the basis of cavernous sinus invasion,[38] [Table 4]B. These classifications incorporated information regarding chiasmal compression and cavernous sinus invasion, which might influence need of surgical intervention.[39] In 2013, another innovative classification introduced by Trouillas et al. [Table 5] was based on tumor invasion determined by imaging and surgical findings and markers of proliferation (Ki-67 and p53). This clinicopathological classification indicates aggressiveness, disease progression, and possibility of recurrence of the tumor.[40]
Table 4: Various Classifications of Pituitary Adenoma

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Table 5: Trouillas Clinicopathological Classification of Pituitary Adenoma[40]

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  Who (2016 and 2017) - Classification of Pituitary Tumors Top


Pituitary neuroendocrine tumors

Basis of new classification and new nomenclature: The main basis of new classification of tumors of anterior pituitary gland is adoption of pituitary adenohyphophyseal cells as the key factor. Several indispensable TFs involved in adenohypophysial cell differentiation and maturation are now regarded as key diagnostic tools for the further characterization of pituitary adenomas [Table 6].[41] Consequently, now the term “hormone-producing pituitary adenoma” has been discarded and pituitary adenohypophyseal cell lineage designation has been adopted for the same. So, the new designations based on cell lineage of differentiation are somatotroph adenomas, lactotroph adenomas, thyrotroph adenomas, gonadotroph adenomas, corticotroph adenomas, plurihormonal adenomas, and null cell adenoma (no cell lineage is yet determined and is a diagnosis of exclusion of sellar tumors).
Table 6: Adenohypophyseal Cells Lineage.Basis of New Classification

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Recognition of new IHC markers in addition to hormonal IHC and transcription factors: Further subclassification of pituitary adenoma is done according to histomorphology and combinations of various IHCs, They have emphasized the use of low molecular weight keratin (CAM5.2), whose pattern of staining and presence or absence of fibrous bodies can be useful in subclassification of these tumors.[42],[43],[44],[45] Hence, the need for ultrastructural analysis for the classification of these tumors has been decreased. Adenohypophyseal cell lineages and their specific transcription factors are summarized in [Figure 2]. For gonadotroph adenoma (SF-1+), no further testing with LH or FSH is required, since there is no clinical relevance for the percentage of these cells. Densely granulated corticotroph adenoma (DGCA) shows diffuse positivity with PAS and ACTH, whereas sparely granulated corticotroph adenoma (SGCA) is weakly positive for periodic acid schiff (PAS)and ACTH. In Crooke cell adenoma, cells have Crooke cell phenotype and ring like positivity with CAM5.2 and relocation of PAS-positive and ACTH-sensitive granules to the periphery of cell membrane and to paranuclear zone. Distinction between densely granulated somatotroph adenoma (DGSA) and sparsely granulated somatotroph adenoma (SGSA)is crucial because DGSA responds well to somatostatin analog, whereras SGSA is associated with clinically aggressive behavior and does not respond to somatostatin analogue. Mixed somatotroph–lactotroph adenoma on staining with CAM5.2 shows pattern, which depends upon GH component whether densely or sparsely granulated. Mammosomatotroph mostly shows perinuclear staining with CAM5.2 (fibrous bodies are rare). Hallmark of plurihormonal PIT-1-positive adenoma (formally known as silent subtype 3A adenoma) is PIT-1 positivity and presence of nuclear spheridia, which can be appreciated on hematoxylin and eosin stained slides.[46] On staining with CAM5.2, mostly perinuclear pattern is seen (occasional fibrous body or negative stain can be present). The differentiating point between PIT-1plurihormonal adenoma and other adenoma containing GH is presence of focal or patchy positivity with GH IHC in the former.[27]
Figure 2: Diagrammatic Representation of Adenohypophyseal Lineages with Their Specific Transcription Factors.

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Older redefined entity: New definition of the null cell adenoma as a “pituitary adenoma that has no immunohistochemical evidence of cell-type-specific differentiation by using pituitary TFs and adenohypophyseal hormones.[47] That means it is negative for both, hormones as well as for transcription factors. It has also been proposed it as diagnosis of exclusion.[46] This is the reason why it is important to differentiate it with the other neuroendocrine tumors of the same location (paraganglioma). The latter will be positive for tyrosine hydroxylase and dopamine–hydroxylase, whereas negative for pituitary-specific TFs.[48],[49],[50] Also, there is loss of cytoplasmic granular succinate dehydrogenase (SDH) expression in paragangliomas.[48],[49]

According to previous definition of null cell adenoma, it accounted for almost 10% of pituitary adenoma,[51],[52] but now after redefining null cell adenoma its incidence has decreased to <1%.[53]

Newly added entity – pituitary blastoma: It is a rare pituitary embryonal tumor that occurs exclusively in children <24 months of age. Mostly, the clinical presentation is due to pressure symptoms and of Cushing's disease, which is actually unusual in this age group. This is caused by mutation in DICER1 gene, a part of DICER syndrome or pleuropulmonary blastoma (familial tumor and dysplasia syndrome).[54] On histomorphology, epithelial glands with rosette formation resembling immature Rathke's epithelium, small immature cells with blastemal-like appearance, and large secretory epithelial cells are appreciated. Majority of these tumors express ACTH and only a few express GH.[55]

For accounting clinically aggressive adenoma, the assessment of tumor proliferative potential which is done by counting mitotic figures, Ki-67, and other clinical parameters (tumor invasion) as well as magnetic resonance imaging findings are utilized.[56]

Recognition of few high-risk pituitary adenomas, which signify elevated risks of recurrence, owing to the clinical aggressive behavior. These include the sparsely granulated somatotroph adenoma, the lactotroph adenoma in men, the Crooke's cell adenoma, the silent corticotroph adenoma, and the newly introduced plurihormonal PIT-1-positive adenoma (previously known as silent subtype III pituitary adenoma).[40]

Previously, atypical adenoma was defined as a tumor with histological features of aggressive adenoma along with raised mitotic count (≥3%), Ki-67 labeling index >3% and overexpression of p53 protein by IHC. In new classification the term “atypical pituitary adenoma,” has been discarded, since it lacks reproducibility and does not predict its relapse and resistance to medical treatment.[57]

Tumor invasion and aggressive adenoma: Tumor invasion is assessed by a) histopathology, b) radiology (Knosp grading), and c) intraoperative findings.[58] Aggressiveness is defined by several parameters, which include a) a large rapidly growing invasive tumor, b) a tumor, which is resistant for medical therapy, c) recurrent tumor despite gross total resection.[59] Cases of clinically aggressive tumors should be closely followed up and vigorously treated.

  1. Posterior pituitary tumors


    • Craniopharyngioma


      • Adamantinomatous
      • Papillary


    • Granular cell tumor of sellar region
    • Pituicytoma
    • Spindle cell oncocytoma


Key features of latest WHO classification of anterior (2017) and posterior (2016) pituitary tumors are summarized in [Table 7] and all major changes and comparison with older WHO classifications in [Table 8].
Table 7: Key Features of Latest Who Classification of Pituitary Tumors

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Table 8: Comparison of Previous and New Who Classification of Pituitary Tumors

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Molecular genetics and biomarkers of pituitary tumors

  • For the diagnosis of pituitary tumors in current era, integrated approach has been adopted to get better definition of tumor and to provide better targeted treatment. Pituitary adenomas evolve through a multistep and multicausal process, which includes hereditary genetic disposition, specific somatic mutations, and endocrine factors
  • Almost 95% of pituitary adenomas are sporadic. Somatic mutations which have been seen are in


    • GNAS (guanine nucleotide binding protein, alpha stimulating),
    • USB8 (ubiquitin specific peptidase),
    • PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha),
    • GPR 101(G protein-coupled receptors),[23]


  • Only ≤5% constitute familial or hereditary adenomas.[61] Syndromes associated with pituitary adenoma are


    • Multiple endocrine neoplasia (MEN) type 1 (MEN1, 11q13),
    • Carney complex (PPKR1A, 17q22–24, associated with somatotroph or lactotroph adenomas),
    • MEN 4 (CDKN1B, 12p13), and
    • Familial isolated pituitary adenomas (FIPA, gene AIP, 11q13.32)


  • In recurrent tumors, increasing chromosomal imbalances have been demonstrated[62]
  • Somatostatin receptors SSTR2 and SSTR5, (O-6) methylguanine DNA methyltransferase (MGMT), and Mut S homolog 6 (MSH6) are predictive biomarkers for molecular target therapies that can be detected by IHC.[63] SSTR, which are expressed in gonadotrophs may represent potential target of multireceptor somatostatin analogues.[64] While Bengtsson et al. (2015) found that lesser expression of MGMT correlated with better response with temozolomide.[65] Hirohata T et al. (2013) correlated immunopositivity for MSH6 with better response to temozolomide[66]
  • A number of biomarkers have been elucidated for the management of unpredictably behaving pituitary tumors. These are apoptotic index, p53, p21, cell cycle inhibitors, topoisomerase, and markers of angiogenesis as well as proliferative markers like Ki-67[67]


Need of reclassifying pituitary tumors (2017 WHO classification)

  1. This system is more reasonable since based on hormonal immunohistochemistry and specific transcription factors
  2. This establishes more biologically and clinically uniform groups of tumors
  3. Now clinically relevant diagnosis and classification of these tumors can be offered by pathologists
  4. Clinical outcomes can be predicted precisely
  5. Histomorphologically, this classification has also identified pituitary adenomas which have high risk of recurrence. This too will guide clinicians to treat accordingly


Lacunae of latest WHO classification

  1. Due to lack of sensitive and specific TPIT antibody, it is unable to differentiate ACTH negative T-PIT-positive tumors from silent adenomas
  2. Whenever hormone immunostain is weak or doubtful, TFs are highly required for determining pituitary cell lineage
  3. Extensive use of IHC is not economic for most of the countries
  4. Still there are dearth of good, safe, and secure morphological criteria in differentiating tumors, which present subsequently with metastatic disease.[68]
  5. The clinical range of behavior of pituitary adenoma is not precisely reflected by the recent WHO classification of tumors of anterior pituitary gland
  6. The concept of pituitary adenoma has been challenged by a group of experts of 14th meeting of the International Pituitary Pathology Club (November 2016, France) and have proposed the term pituitary neuroendocrine tumor (PitNET), that better recognizes the highly variable impact (biological aggressiveness) of these tumors on patients[68]
  7. Due to lack of standardization of immunohistochemical procedures, shortage of reliable and specific antibodies, and difficulties in interpretation of immunohistochemical stainings, there are still problems in making their diagnosis[41]


Implications for pathologists

The newer practical and reasonable classification of pituitary adenoma integrates clinical and radiological findings with histomorphology and IHC for hormones and TFs. This better classifies and subclassifies pituitary adenoma. Now pathologists can assess clinical aggressive tumors and report accordingly. This will be helpful for clinicians in recognition of these tumors and for providing aggressive postoperative therapy to lessen the recurrence of tumors.


  Conclusion Top


The new WHO classification of pituitary tumors has provided integrated approach for the diagnosis of pituitary neuroendocrine tumors. They are classified according to adenohypophyseal cell lineages determined by IHC of pituitary-specific transcription factor. These are further subclassified by application of low molecular weight cytokeratin (CAM5.2) and hence supplanted electron microscopy for diagnosis of most of pituitary tumors. It has also recognized few high-risk pituitary adenomas, which extend out the risk of recurrence. A newer entity pituitary blastoma has been added, which is seen exclusively in children. The term “atypical pituitary adenoma” has been discarded. Null cell adenoma is being redefined and said to be diagnosis of exclusion. It is crucial to differentiate this entity from other neuroendocrine tumors of the same location (paraganglioma). Emphasis has been given on incorporating other tumors of the sellar region in the differential diagnoses. Two unique molecular profiles of craniopharyngioma have been identified. The other tumors of posterior pituitary, the spindle cell oncocytomas, granular cell tumors, and pituicytomas have been proposed to constitute spectrum of a single nosological entity. There are many merits of this new classification over the previous one, but there are still a few lacunae that need to be addressed in further editions.

Financial support and sponsorship

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Conflicts of interest

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