Classification And Clinical Presentation

Many classification schemes have been used to stratify pituitary tumors. These have included clinical, pathologic, and imaging-based classifications, many of which are still in use informally.

In an attempt to standardize reporting, the World Health Organization approved a five-tier classification based on (1) clinical presentation and secretory activity, (2) size and invasiveness (i.e., microadenoma versus macroadenoma), (3) histologic features, (4) immunohistochemical profile, and (5) ultrastructural features on electron microscopy.7 This integrates many of the prior schemes and provides a practical, comprehensive method for describing pituitary tumors (Table 47-1).

Nonfunctioning adenomas account for 25% to 30% of pituitary adenomas seen in clinical practice. These tumors have also been referred to in the past as chromophobe adenomas, because they do not stain with hematoxylin and eosin (H&E).

Nonfunctioning pituitary tumors typically cause signs and symptoms of mass effect on surrounding structures. Bitemporal hemianopsia, loss of visual acuity, and chronic headache are all commonly described. A thorough visual-field examination is essential. Signs of cavernous sinus compression with facial pain, diplopia, and anisocoria may also occur.

These tumors do not secrete active hormones, and therefore signs of hormone excess are absent. Prolactin levels may be mildly elevated because of the "stalk effect," resulting from loss of tonic inhibition from the hypothalamus caused by compression or distortion of the pituitary stalk. Varying degrees of hypopituitarism may also be seen, and a full panel of hormone levels should be drawn. Signs of hormone insufficiency include decreased libido, fatigue, weakness, and hypothyroidism. It is essential to draw thyroid hormone levels in addition to thyroid-stimulating hormone (TSH) levels, because the patient with hypothyroidism of pituitary etiology will likely have a low TSH.

Prolactin-secreting tumors are the most common pituitary adenoma, responsible for approximately 27% of pituitary tumors.5 They occur more often in women by nearly 2:1, but autopsy studies reveal an almost equal prevalence of pro-lactinomas in both sexes. Prolactinomas often cause amenor-rhea or galactorrhea and infertility in women of childbearing age. In men, infertility, decreased libido, and impotence are seen. In both men and women, secondary endocrine dysfunction can occur (Table 47-2).

Serum prolactin levels at diagnosis are usually markedly elevated and correlate with tumor size. As mentioned previously, prolactin elevation from pituitary stalk compression alone is rarely greater than 150 ng/mL. In addition, most patients show evidence of secondary hypogonadism in addition to elevated prolactin values.

TABLE 47-1 World Health Organization Classification of Pituitary Tumors

I. Clinical Presentation and Secretory Activity

A. Endocrine Hyperfunction

1. Acromegaly/gigantism, elevated growth hormone levels

2. Hyperprolactinemia and sequelae

3. Cushing's disease, elevated serum ACTH and Cortisol levels

4. Hyperthyroidism with inappropriate secretion of thyrotropin

5. Significantly elevated follicle-stimulating hormone and luteinizing hormone

6. Multiple hormonal overproduction

B. Clinically Nonfunctioning

C. Functional Status Undetermined

D. Endocrine Hyperfunction Due to Ectopic Sources

1. Clinical acromegaly secondary to ectopic GHRH overproduction

2. Cushing's disease secondary to ectopic CRH overproduction

II. Size and Invasiveness (e.g., Microadenoma)

A. Location

1. Intrasellar

2. Extrasellar extension

3. Ectopic

B. Size

2. Macroadenoma (>10 mm)

C. Growth Pattern

1. Expansive

2. Grossly invasive of dura, bones, nerves, and brain

3. Metastasizing

III. Histologic Features

A. Adenoma

1. Typical

2. Atypical (pleomorphism, enhanced mitotic activity, high MIB-1 labeling index)

If growth pattern can be evaluated:

1. Expansive

2. Histologically invasive

B. Carcinoma

C. Nonadenoma

1. Primary or secondary nonadenohypophyseal tumors

2. Pituitary hyperplasia

IV. Immunohistochemical Profile Principal Immunoreactivity

4. ACTH

5. FSH/LH/alpha subunit

7. Rare hormone combinations

8. Immunonegative

V. Ultrastructural Features on Electron Microscopy

A. Growth Hormone

1. Densely granulated

2. Sparsely granulated

B. Prolactin

1. Sparsely granulated

2. Densely granulated

C. Growth Hormone-Prolactin

1. Mixed GH and PRL cell

2. Mammosomatotroph cell

3. Acidophil stem cell

D. ACTH

1. Densely granulated

2. Sparsely granulated

3. Crooke's cell variant

1. Male type

2. Female type

F. Clinically Nonfunctioning

1. Nononcocytic

2. Oncocytic

G. Adenomas of Unknown Cell Derivation

1. Silent corticotroph adenoma subtype 1

2. Silent corticotroph adenoma subtype 2

3. Silent corticotroph adenoma subtype 3

4. Others (unclassified plurihormonal)

Secondary Immunoreactivity

PRL, a-subunit, TSH, FSH, LH a-Subunit a-Subunit, TSH LH, a-subunit PRL, GH, ACTH a-Subunit, GH, PRL

ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone.

Source: Based on Kleihues P, Cavenee WK (eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer (IARC), 2000.

Somatotropic adenomas are responsible for the manifestations of gigantism in children and adolescents and acromegaly in adults. The clinical characteristics of these conditions are due to an excess of growth hormone. Acromegaly is characterized by extensive soft-tissue swelling, particularly in the hands, feet, and tongue. This pathophysiology is responsible for the typical body habitus as well as complaints of excessive snoring, sleep apnea, and carpal tunnel syndrome.

In addition, acromegaly is associated with cardiomyopathies, hyperlipidemia, and abnormal serum glucose regulation, which pose significant health risks and morbidity if growth hormone hypersecretion is not corrected.

Corticotrophic adenomas constitute approximately 10% of pituitary adenomas in surgical series, and occur nearly five times more often in women than men.5 Clinically, corticotrophic adenomas are responsible for Cushing's disease, characterized by pituitary-dependent hypercortisolism and a typical body habitus of moon facies, prominent supraclavicu-lar fat pads, abdominal striae, centripetal obesity, acne, easy bruising, hirsutism, hypertension, glucose intolerance, and emotional lability (see Table 47-2).

Corticotrophic adenomas often present a diagnostic dilemma for clinicians, because their imaging characteristics and laboratory abnormalities are variable. Tumor size appears to have no correlation with severity of hypercortisolism, and the tumor is often not seen on imaging studies before surgery. Thus in all patients a thorough laboratory investigation must be performed to confirm the diagnosis preoperatively, especially where tumor is not obvious on imaging studies. Determinations of serum cortisol, adrenocorticotropic hormone (ACTH), 24hour urine free-cortisol, high- and low-dose dexamethasone

Table 47-2

Common Clinical Presentations of Pituitary Adenomas

Hypersecretion

GH-secreting adenoma: acromegaly ACTH-secreting adenoma: Cushing's disease; Nelson's syndrome

Prolactin-secreting adenoma: amenorrhea-galactorrhea TSH secreting adenoma: secondary hyperthyroidism

Pituitary insufficiency

Symptoms: diminished libido, fatigue, weakness, hypothyroidism

Mass Effect

Optic chiasm: bitemporal visual-field deficit and possibly diminished acuity Cavernous sinus: trigeminal nerve ^ facial pain; cranial nerves III, IV, VI ^ diplopia, ptosis, anisocoria Dura or diaphragma sellae: headache Hypothalamus: behavior, eating, and vigilance disturbances Temporal lobe: complex partial seizures

Incidental

Evaluation for headaches, trauma, nasal sinus disorders

ACTH, Adrenocorticotropic hormone; GH, growth hormone; TSH, thyroid stimulating hormone.

suppression tests, and corticotropin-releasing hormone stimulation tests are most commonly used to make the diagnosis of Cushing's disease. These tests are used to differentiate Cushing's syndrome of pituitary origin from adrenal tumors and ectopic ACTH secretion, which appear similar (Table 47-3). If these tests are inconclusive or tumor is not seen on magnetic resonance imaging (MRI), inferior petrosal sinus sampling is used to confirm the diagnosis and provide a rough estimate of lateralization to guide surgical dissection.

Thyrotrophic adenomas are rare and account for only 1% of pituitary adenomas. They occur with equal frequency in all age groups, without male or female predominance. Two types of these tumors are commonly noted: those producing excessive TSH, causing clinical hyperthyroidism, and those occurring in the setting of thyrotroph hyperplasia caused by chronic hypothyroidism.5

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