Somatotroph Adenomas

 Somatotroph adenomas arise from Pit- 1 pituitary cell lineage and express GH in excess. Approximately 15% of surgically removed pituitary adenomas represent pure GH cell adenomas [15]. Most of these tumours are associated with clinical signs of acromegaly, but silent forms have also been reported. According to the density of GH- containing secretory granules in the cytoplasm of the cells, somatotroph adenomas can be densely or sparsely granulated. The clear distinction between them is crucial for proper prognosis and treatment.

Densely granulated somatotroph adenomas occur with the same frequency in both sexes peaking at the same time (in the sixth decade). The tumours display slow, expansive growth resulting in the typical ‘ballooning of the sella’ and may remain intrasellar for several years. Histologically, the densely granulated form is strongly acidophilic displaying diffuse or, less frequently, trabecular pattern. Extensive immunoreactivity for GH is usually accompanied by similarly strong positivity for α- subunit. Scattered immunopositivity for PRL and β- TSH is usually not associated with oversecretion of these hormones. Immunostaining for Cam5.2 demonstrates a diffuse perinuclear pattern.

Sparsely granulated somatotroph adenomas are diagnosed earlier, peaking in the fourth decade. The tumours tend to be macroadenomas at the time of diagnosis and are often invasive.

Histology identifies chromophobic adenomas invariably displaying a diffuse pattern; GH immunoreactivity is often sparse. Nuclear pleomorphism may be evident, and adenoma cells harbour a homogeneous, spherical, juxtanuclear, practically unstained structure. This fibrous body is strongly immunopositive for Cam5.2 in a characteristic dot pattern and is the best histological marker for this tumour type since it is present in more than 70% of the cells. As op posed to the densely granulated type, multiple immunoreactivities for pituitary hormones are rarely noted in sparsely granulated somatotroph adenomas.

Mixed somatotroph and lactotroph adenomas, comprised of two distinct cell types, account for approximately 5% of surgically removed adenomas. The tumours are associated with acromegaly and varying degrees of hyperprolactinaemia. They tend to be aggressive and are difficult to treat. Mixed adenomas usually consist of densely granulated GH cells and sparsely granulated PRL cells. Accordingly, they are composed of acidophilic and chromophobic cells, displaying immunoreactivity for GH and PRL; α- subunit positivity is also frequent in this tumour type. Other combinations may occur, but they are rare.

The infrequent (2%) mammosomatotroph cell adenomas are monomorphous, consisting of one cell type displaying markers of both GH and PRL differentiation. Clinically they are associated with acromegaly and mild hyperprolactinaemia. These acidophilic tumours are immunoreactive for GH and α- subunit and, to a lesser extent, for PRL. At the ultrastructural level, the densely granulated tumour cells possess unusually large (up to 1000 nm and over) secretory granules and display lateral granule extrusions which is a PRL cell marker. The slow- growing mammosomatotroph adenomas show biological behaviour similar to densely granulated somatotroph adenomas.

Morphologic effects of treatment with long- acting somatostatin analogues are neither severe nor consistent. Remarkable shrinkage of cells and marked fibrosis are infrequent. Most common findings include the increase in size and number of secretory granules and in creased lysosomal activity while significant fibrosis is less frequent. The close correlation observed between clinical response and tumour morphology in cases of prolactinomas treated with dopamine agonists does not exist in examples of somatostatin analogues therapy.

Both types of GH cell adenoma may engage in focal production of endocrine amyloid. Approximately 2– 3% of morphologically typical sparsely granulated GH cell adenomas are clinically silent, the reason for which is unknown. Few cases of the sparsely granulated tumours contain variable amounts of nervous tissue (neuron- like cells and neuropil) as a likely result of neuronal differentiation within the adenoma. This variant is known as neuronal metaplasia.

Lactotroph Adenomas

Lactotroph adenomas arise from the Pit- 1 pituitary cell lineage and express mainly PRL. They are classified into three histological sub types: sparsely granulated lactotroph adenomas, densely granulated lactotroph adenomas, and acidophil stem cell adenomas.

Sparsely granulated lactotroph adenomas are the most common adenoma type accounting for 27– 30% of pituitary tumours. They are associated with hyperprolactinaemia, primary or secondary amenorrhoea, galactorrhoea, and infertility in women. The less specific symptoms in men— decreased libido and impotence— usually mean a delay in diagnosis and development of macroadenomas whereas the majority of tumours in women are small and classified as microadenoma. In both sexes, lactotroph adenomas are most frequent in the third and fourth decade of life. However, the incidence of this tumour type is significantly higher in women in their childbearing years. Lactotroph adenomas are associated with wide- ranging biological behaviours from indolent to highly aggressive, and in men usually present invasive radiological features. The PRL blood levels are roughly proportional to the tumour mass. Histologically, most lactotroph adenomas are chromophobic with a diffuse pattern. Immunostaining demonstrates strong PRL immunopositivity tracing the sacculi of the prominent Golgi apparatus (Golgi pattern). Ultrastructurally, the three salient features are masses of rough endoplasmic reticulum, prominent Golgi apparatus, and lateral extrusion of the small, sparse secretory granules— misplaced exocytosis. The latter is a specific marker of PRL differentiation.

Densely granulated lactotroph adenomas display strong and diffuse PRL immunoexpression with coexpression of Pit- 1 and ER- α. They are rare and have been considered aggressive tumours.

Acidophil stem cell adenomas are rare (2%), monomorphous type tumours with morphological signs of PRL and GH differentiation. The tumours are associated chiefly with hyperprolactinaemia, but the serum PRL levels may be disproportionately low for its size. Physical stigmata of acromegaly and significant elevation of GH levels are infrequent. These tumours grow aggressively in young subjects with a tendency to invade intrasellar areas. The histological analysis demonstrates chromophobic adenomas with moderate to strong immunoreactivity for PRL. Immunopositivity for GH is weak or negative, but immunostaining for cytokeratin reveals the dot- like positivity of fibrous bodies. The striking ultra structure is characterized by oncocytic change with the formation and increased number of giant mitochondria, sparse and small secretory granules with lateral extrusion (PRL marker), and fibrous bodies (GH marker).

Although calcification is extremely rare in other adenoma types, an estimated 10– 15% of lactotroph adenomas display varying degrees of calcification. The alteration may be extreme (‘pituitary stone’). Deposition of endocrine amyloid occurs infrequently.

Adequate therapeutic response with dopamine agonists is associated with striking morphological changes in adenoma cells: the nucleus becomes heterochromatic, the cytoplasm shows marked shrinkage due to loss and involution of the hormone- producing apparatus of the cell (rough endoplasmic reticulum, Golgi complex), and PRL immunoreactivity is reduced or lost. Theoretically, the morphological changes are reversible; however, portions of the neo plasm may permanently lose their responsiveness and retain their suppressed features even when treatment is discontinued. Long- term administration of dopamine agonists may also cause varying degrees of fibrosis and calcification—which presents as psammoma bodies.

thyrotroph Adenomas

Thyrotroph adenomas express mainly TSH and also arise from Pit- 1 pituitary cell lineage. They represent 1% of surgically removed adenomas and are associated either with hyperthyroidism or inappropriately elevated levels of TSH. Inexplicably, some tumours bearing immunohistochemical characteristics of thyrotroph adenomas occur in euthyroid subjects. At the time of diagnosis, these tumours are often macroadenomas with a tendency to invade. The morph ology of the small group of thyrotroph adenomas exhibits surprising diversity. Histologically, the adenomas are chromophobic and negative, or mildly positive with PAS. They may be highly differentiated comprising elongated polar cells forming pseudorosettes around vessels. Alternatively, the pattern may be diffuse in some cases with considerable nuclear pleomorphism. However, another variant is markedly fibrotic. Minute calcifications may be evident as well. Immunoreactivity for TSH is variable; it is often patchy or scattered, rarely extensive. Scattered cells may exhibit immunoreactivity for GH, PRL, and α- subunit. Both Pit- 1 and GATA2 are expressed. Thyrotroph adenomas possess somatostatin receptors and, in most cases, they are strongly positive for somatostatin receptor 2 (SSTR2) immunostaining.

Monomorphous Plurihormonal Adenomas

Plurihormonal adenomas produce more than one hormone. They can be monomorphous or plurimorphous, consisting of two or more different cell lineages. They include plurihormonal Pit- 1 positive adenomas previously called silent subtype 3 adenomas. They have a frequency of approximately less than 1% and are clinically significant owing to their aggressive behaviour. This tumour type is equally frequent in both sexes, but it has a strikingly different age- related distribution. In men, they may occur at any age from the second to the seventh decade while in women it occurs between the second and fourth decade, peaking in the late twenties, but rarely occurring after 40 years of age. Plurihormonal Pit- 1 positive adenomas can mimic lactotroph adenomas in women and are associated with low- grade hyperprolactinaemia. Some cases may present with acromegaly. Histologically, they are often acidophilic and may show mild PAS positivity. The large adenoma cells form a diffuse, or lobular pattern. Immunohistochemistry may demonstrate scattered, minor positivity for various adenohypophyseal hormones, but the majority of tumour cells are immunonegative for all known pituitary hormones, showing extensive nuclear expression of Pit- 1.

Molecular Pathology of the Pit-1 Family of tumours

Approximately 40– 60% of sporadic somatotroph adenomas pre sent somatic mutations in the gene encoding the α subunit of the stimulatory G- protein (GNAS). These mutations are commonly found in densely granulated somatotroph adenomas. The somatic activating mutations, known as gsp mutations, prevent hydrolysis of guanosine- 5’- triphosphate (GTP), leading to a constitutive activation of the cAMP pathway, which in somatotrophs increases GH secretion and cell proliferation. A hallmark of somatotroph adenomas is the genetic and epigenetic alterations in the GNAS gene with the ensuing dysregulation of the cAMP pathway. Somatotroph adenomas with gsp mutations tend to have higher serum GH and IGF- I, but there are no differences between sparsely and densely granulated subtypes. Epigenetic alterations that are common to both somatotroph and lactotroph adenomas include CASP8, CDKN2A, DAPK1, MGMT, RB1, and TP73.

AIP- mutation positive patients present with somatotroph and lactotroph adenomas in 85% of the cases. In MEN 1, lactotroph adenomas are the most frequent, followed by clinically non- functioning adenomas, somatotroph and corticotroph adenomas. In thyrotroph adenomas, inactivating mutations of MEN1 gene have been reported.

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مواضيع ذات صلة

T pit Family of tumours

Pituitary Adenomas

Molecular Mechanisms of Carcinogenesis

Chronic Myeloid Leukemia, BCR-ABL Gene, and Disease Monitoring

Application of Liquid Biopsy to Non-small- Cell Lung Cancer Lung

Circulating Tumor DNA

Biomarkers in the Blood and in Tissues: A Complementary Approach

Biomarkers in Oncology: An Evolving Concept

Clinical Development of Venetoclax for Acute Myeloid Leukemia

Clinical Development of Oblimersen for Acute Myeloid Leukemia

Modalities for treating cancer

Tumor markers