39.3.1 Classification

PAs can be classified according to multiple criteria, including radiological, histopathological, immunohistochemical, clinical, functional, and tumor dimensions.15 ^,​ 16 ^,​ 17 One of the earliest classification systems for PA was proposed by Hardy18; it was based primarily on sellar enlargement with or without bony destruction and on the pattern/symmetricity of tumor extension. Subsequently, Kovacs and Horvath19 presented another classification based on the ultrastructural details of the tumor as highlighted on electron microscopy. The more recent Knosp classification20 is based on the radiological extent of cavernous invasion by the tumor and its precise relationship to the cavernous carotid artery. These classification schemes do not take into account subtyping based on hormonal expression by tumor cells. Advancements have enabled the evolution of pathological classification of PA from a histochemical classification (i.e., acidophilic, basophilic, and chromophobic PA) to an immunohistochemical-based one (i.e., lactotrophic, somatotrophic, corticotrophic, gonadotrophic, thyrotrophic, and null cell adenomas).15 Electron microscopy has further helped delineate additional subtypes based on the arrangement of ubiquitous cytoplasmic constituents and appearance of specific morphology.

Besides the enzymatic immunohistochemistry (IHC) assay, the functional status of the tumor is defined primarily by the clinical symptoms produced by hormonal hypersecretion. Clinically, a PA can be classified as either functional (hormone-secreting) or nonfunctional (non–hormone-secreting). Functional tumors can manifest clinically as acromegaly (GH excess), Cushing’s disease/Nelson’s syndrome (ACTH excess), Forbes-Albright syndrome (prolactinoma, Prl excess), or secondary hyperthyroidism (TSH excess). PA can be classified on the basis of the tumor dimensions into microadenoma (≤ 1 cm) and macroadenoma (> 1 cm).3 Some authors have labeled macroadenomas that are larger than 4 cm in any dimension as giant PAs.

39.3.2 World Health Organization Grading

The currently valid 2016 World Health Organization (WHO) classification system employs the use of modern sensitive enzymatic assays to ascertain the hormonal expression in PA apart from the histopathological ultrastructural details identified on electron microscopy.21 This classification differentiates PA into three histopathological grades that also correspond to their associated biological behavior: typical benign adenomas, atypical adenomas, and PCs.16 Classical or typical PA is the most commonly observed variant and has the lowest growth potential. Atypical adenomas, accounting for approximately 2.7 to 15% of PA, represent an intermediate-grade tumor exhibiting more aggressive biological behavior, an increased growth potential, and a higher likelihood of tumor recurrence. They are characterized by a Ki-67 labeling index > 3%, excessive p53 immunoreactivity, and an increased rate of mitosis. In addition, invasiveness of the tumor is another essential criterion for the diagnosis of atypical adenoma.2 ^,​ 15 ^,​ 22 PC is the most aggressive variant, demonstrating malignant behavior with evidence of cerebrospinal or systemic metastases. It is a rare entity, accounting for < 1% of symptomatic pituitary tumors. Although de novo development of PC cannot be excluded, in most cases PC arises from a preexisting macroadenoma exhibiting invasive and proliferative features. The usual latency period for the development of PC from its benign variant is 7 years, although it varies depending on the tumor subtype.2 ^,​ 15 ^,​ 22

Limitations of Current WHO Grading: Invasion and Proliferation

One of the major caveats to the currently valid WHO grading system is the linkage of proliferation parameters to tumor invasiveness when defining atypical adenomas.15 ^,​ 16 ^,​ 23 ^,​ 24 This creates two specific groups of tumors within the classification of typical PA, one having proliferative-only characteristics and other invasive-only. Both these tumor groups will be classified as WHO grade I benign PA, but their biological behavior, natural history of progression, and tumor recurrence rates are quite different from typical PA, being neither invasive nor proliferative. Accordingly, based on the French collaborative study on prognostic factors for PA, Trouillas et al24 proposed a new five-grade classification scheme for PA, attempting to reclassify invasive tumors and segregate them from proliferative ones so as to better predict the long-term functional outcome within each tumor grade. Besides uncoupling the invasiveness and proliferation, they also precisely defined the diagnostic prerequisites for invasiveness and proliferative tumors. Invasion is defined as histological and/or radiological (MRI) signs of cavernous sinus (Fig. 39.2) or sphenoid sinus invasion (Fig. 39.3). Proliferation is defined as the presence of at least two of three criteria: Ki-67 labeling index > 1% (Bouin-Hollande fixative) or > 3% (formalin fixative); mitoses, n > 2/10 per high-powered field; and p53 positive (> 10 strongly positive nuclei).24 Similarly, Saeger et al16 have also proposed another modification to the currently valid WHO grading that highlights the importance of segregating invasiveness and proliferation as prognostic markers.

39.3.3 Pathogenesis and Biomarkers of Tumor Aggressiveness

Although the precise molecular mechanisms involved in the pathogenesis of PA are unknown, it is now accepted that PA onset is related to proto-oncogene mutations, overexpression of activating genes, or loss of tumor suppressor genes.4 The initiating events lead to proliferative gain of function in a single monoclonal pituitary cell population, subsequently leading to clonal expansion by tumor-promoting molecules.4 Recent evidence points toward a pivotal role for epigenetic modifications, microRNAs, and long noncoding RNAs in the pathogenesis of PAs.4 One of the most important prognostic factors for PAs is the accurate classification of tumor based on hormone content and subtyping with reference to ultrastructural details. Biomarkers of aggressiveness primarily include histological subtype, Ki-67 labeling index, p53 expression, and markers of invasion and proliferation.6 ^,​ 15 ^,​ 22 PA variants often associated with aggressive natural history include densely granulated lactotroph adenomas, acidophil stem cell adenomas, sparsely granulated somatotroph adenomas, thyrotroph adenomas, Crooke’s cell adenomas, sparsely granulated corticotroph adenomas, null cell adenomas, and silent subtype 3 adenomas.6 ^,​ 15 ^,​ 22 Other novel markers potentially acting as surrogates for aggressive biological behavior include genomic imbalance (11q allelic loss), DNA aneuploidy, germline mutations associated with MEN1 (multiple endocrine neoplasia-1), MEN 4, Carney’s complex, familial isolated PA and succinate dehydrogenase syndrome, micro-RNAs, p27, senescence markers (p16, p21, β-galactosidase), growth factors (epidermal growth factor, vascular endothelial growth factor) and their receptors (EGFR, VEGFR), matrix metalloproteinase, neural cell adhesion molecule, and Galectin-3.6 ^,​ 15 ^,​ 22 Apart from these syndromes, familial clustering of pituitary tumors has also been reported in the Utah population.25

39.4.1 Pituitary Incidentaloma and Nonfunctional Pituitary Adenoma

With the advent and widespread availability of better neuroimaging modalities and more frequent cranial screening performed for unrelated causes, an increasing number of PAs are being diagnosed incidentally.26 These “incidentalomas” are not necessarily asymptomatic, although they are almost always nonfunctional in nature.27 They are associated with pituitary dysfunction in about 15% of patients and with visual deficits in about 5% of patients. Although the majority of these tumors are microincidentalomas, approximately a third are macroincidentalomas, which may demonstrate significant increase in size over time and will require some intervention. On the contrary, nonfunctioning microincidentalomas smaller than 5 mm usually do not grow much and rarely require active intervention other than radiological surveillance. Only 5% of microincidentalomas exceed 10 mm size in their natural course of disease.27

Nonfunctioning pituitary macroadenomas generally lead to compression of the pituitary gland and some degree of pituitary dysfunction. GH deficiency is the most frequent abnormality, followed by gonadotropin (LH, FSH), ACTH, and TSH deficiencies.6 ^,​ 28 Marginal elevation of serum Prl levels (usually up to 100 ng/mL, occasionally more) can be seen with nonfunctioning macroadenomas because of the loss of the inhibitory effect of dopamine from the hypothalamus on Prl secretion, a phenomenon known as “stalk effect.”6 ^,​ 28 The risk of apoplexy is minimal (1%, and 10% at 5 years) but is greater in macroadenomas adjacent to optic apparatus, and especially in those requiring anticoagulation therapy.6 ^,​ 28 Direct mass effect may lead to visual decline and is the most common presenting complaint of adults who have nonfunctioning macroadenomas.

39.4.2 Acromegaly

Clinical manifestations of acromegaly include coarsening of facial features, malocclusion of teeth, prognathism, and enlargement of forehead, tongue, hands and feet. Onset of GH excess from tumor secretion prior to fusion of the bony epiphysis will result in gigantism (Fig. 39.4). Complications linked to GH and IGF-1 excess in acromegaly include premature atherosclerosis, hypertrophic cardiomyopathy, diabetes mellitus, arthritis, polyps of the colon, carpel tunnel syndrome, and obstructive sleep apnea syndrome.29 ^,​ 30 Serum GH and IGF-1 levels screen for acromegaly, and an oral glucose tolerance test confirms the diagnosis.29 ^,​ 30 ^,​ 31 ^,​ 32 Current consensus guidelines published in 201031 unanimously accept the biochemical remission criteria as normalization of age-adjusted IGF-1 levels plus either a random GH < 1 μg/L in patients treated medically or glucose-suppressed GH < 0.4 μg/L in patients treated using other modalities, except pegvisomant (GH receptor antagonist), for which only IGF-1 levels are used.

39.4.3 Cushing’s Disease

Cushing’s disease is characterized by excessive ACTH secretion by PA, leading to surplus cortisol secretion by the adrenal glands and ultimately resulting in diabetes mellitus, hypertension, cardiovascular disease, hypercoagulability, weight gain, central obesity, moon facies, abdominal purple striae, easy bruisability, increased facial and body hair, osteoporosis, proximal muscle weakness, and neurocognitive and psychiatric disturbances.8 ^,​ 33 Although rare, Cushing’s disease is associated with significant clinical, social, economic, and quality-of-life burdens. Frequently, the diagnosis is delayed because of the gradual presentation of the constellation of heterogeneous clinical signs and symptomatology, which present over a period of a couple years.8 ^,​ 33 Per Endocrine Society Clinical Practice Guidelines,34 ^,​ 35 screening tests to diagnose Cushing’s disease include 24-hour urinary free cortisol excretion test, midnight salivary cortisol assay, and 1-mg dexamethasone suppression test. To distinguish ectopic ACTH secretion from Cushing’s disease, bilateral inferior petrosal sinus sampling with corticotropin-releasing hormone (CRH) stimulation is the gold-standard test. It has a sensitivity of 80 to 100% and a specificity of more than 95%.34 ^,​ 35 ^,​ 36

Because baseline central–peripheral gradients have suboptimal accuracy, CRH/desmopressin stimulation must be performed for optimal results. However, this test has a limited role in lateralizing the tumor.34 ^,​ 35 ^,​ 36 The false-negative results in this test can occur because of unilateral or bilateral anatomical variants in the petrosal venous system. Jugular venous sampling is another less invasive alternative for this test34 ^,​ 35 ^,​ 36; however, the high-dose dexamethasone suppression test is much more readily available, less invasive, and dynamic. A screening MRI/CT scan of the chest and abdomen is recommended when looking for a primary malignancy with ectopic ACTH production.34 ^,​ 35 ^,​ 36

Criteria for biochemical remission for Cushing’s disease after surgery are affected by perioperative use of injectable steroids and the use of adjuvant medical therapy in the form of metyrapone, ketoconazole, and mifepristone, which has resulted in the lack of a universal definition for endocrine remission.8 ^,​ 33 To streamline the criteria, the Endocrine Society clinical practice guideline published in 200833 advised withholding perioperative or postoperative glucocorticoids until testing for biochemical remission is complete. They recommended that a postoperative day 1 morning serum cortisol < 2 μg/dL is an indication of remission.33 In addition, close monitoring for any signs of hypoadrenalism should be performed during the immediate postoperative period, and a maintenance dose glucocorticoid replacement should be instituted as soon as biochemical remission is proven. This replacement may need to be continued for approximately 6 to 18 months.33

Patients who have serum cortisol levels between 2 and 5 μg/dL are also considered to be in possible remission, because their tumor recurrence rates are similar to those in patients who have cortisol levels < 2 μg/dL (estimated at approximately 10% at 10 years postoperatively).33 Nevertheless, this subset of patients is referred to as having subclinical Cushing’s disease. They are advised to undergo repeat serum cortisol testing more frequently than those who have definite remission criteria. Patients who have serum cortisol levels persistently exceeding 5 μg/dL up to 6 weeks after surgery are considered to have persistent disease and should be considered for repeat surgery, adjuvant radiation, or medical-based therapies.33 Besides other supplementary diagnostic tests (such as 24-h urinary free cortisol levels), midnight salivary cortisol levels, serum ACTH levels, and low-dose dexamethasone suppression tests can also be performed to confirm the endocrine remission.8 ^,​ 33 Apart from these static biochemical tests, further dynamic biochemical tests such as CRH stimulation test, desmopressin stimulation test, and metyrapone stimulation tests can also be performed, although these tests have no specific advantage over the more traditional static tests.8 ^,​ 33 ^,​ 37

39.4.4 Prolactinoma

Prolactinomas are associated with endocrine dysfunction, which affects gonadal function, and neurological deficits caused by mass effect. Their clinical manifestation includes Forbes-Albright syndrome, including amenorrhea, galactorrhea, and infertility in women. In men, it presents as decreased libido, sexual dysfunction, erectile dysfunction, infertility, and occasionally gynecomastia.12 ^,​ 13 ^,​ 14 In addition, hypoestrogenism and hypoandrogenism associated with hyperprolactinemia can lead to osteoporosis in both sexes. Serum Prl levels can rise because of any pituitary tumor causing compression on the posterior pituitary gland (“stalk effect”).12 ^,​ 13 ^,​ 14 However, serum Prl levels > 100 ng/mL are suggestive of prolactinoma, and serum levels > 200 ng/mL are highly suggestive of Prl-secreting tumor. Serum Prl levels of 100 to 250 ng/mL suggest the presence of a microprolactinoma, and levels > 250 ng/mL typically indicate macroprolactinoma.12 ^,​ 13 ^,​ 14 At times even a giant invasive prolactinoma may reveal a serum prolactin level within normal range. This phenomenon, known as the “hook effect,” occurs because of oversaturation of a prolactin-detecting antibody assay. Accordingly, to appropriately judge prolactin levels, serial dilution assay should also be performed.12 ^,​ 13 ^,​ 14 Other common causes of elevation of serum Prl levels also need to be ruled out; these include pregnancy, primary hypothyroidism, chronic renal failure, liver cirrhosis, drug-induced hyperprolactinemia, pseudoprolactinomas from stalk effect, macroprolactinemia, and physiological elevations.12 ^,​ 13 ^,​ 14 Hence the initial laboratory tests in a case of suspected prolactinoma should include biochemical testing to rule out renal and liver insufficiencies, TSH levels, and a pregnancy test for women. Postoperative day 1 serum Prl level of < 10 ng/mL are associated with nearly 100% cure rates in microprolactinoma patients.

39.4.5 Thyrotropinoma

Thyrotropinomas are rare pituitary tumors that present with the same symptoms as primary hyperthyroidism: palpitations, heat intolerance, increased sweating, restlessness, weight loss, and goiter. They may present with mass effect symptoms and hypopituitarism.10 ^,​ 11 They are often diagnosed late and are usually macroadenomas at the time of presentation. In most of the earlier studies, 70 to 90% of TSH-producing tumors were macroadenomas, with a latency period between onset of symptoms and diagnosis of approximately 4.5 to 9 years.10 ^,​ 11 More recent studies report an increasing proportion of microadenomas at the time of diagnosis. The severity of clinical symptomatology is disproportionately low considering the amount of serum TSH and T4 elevation in thyrotropinomas when compared with corresponding patients who have untreated primary hyperthyroidism. These patients have an increased propensity to develop thyroid cancer because of the uninhibited TSH stimulation of thyroid cells.10 ^,​ 11 Hence periodic screening for thyroid nodules using high-resolution ultrasound is recommended to detect the possible development of thyroid cancer. This diagnosis is usually considered when the TSH levels are inappropriately elevated or normal in a hyperthyroid individual who has increased serum T4 levels, regardless of presence of visible tumor on imaging.10 ^,​ 11

The differential diagnosis includes early phase of destructive thyroiditis, inconsistent thyroid replacement of hypothyroidism, recurrence of primary hypothyroidism, assay interference with heterophilic antibodies, acute psychiatric disease, use of amiodarone medication, and genetic causes, including resistance to thyroid hormone (RTH α and β), elevated serum thyroid hormone-binding proteins, and familial dysalbuminemic hyperthyroxinemia.10 ^,​ 11 Undetectable TSH levels 7 days after surgery are highly predictive of successful outcome.

39.4.6 Pituitary Apoplexy

Pituitary apoplexy is a rare but sometimes life-threatening condition caused by infarcts or bleeds within the pituitary tumor, leading to both acute hypopituitarism and rapidly expanding intracranial mass, which may cause permanent visual loss if not treated immediately.38 ^,​ 39 ^,​ 40 ^,​ 41 Pituitary apoplexy has an estimated prevalence of 6.2 cases per 100,000 persons and an incidence of 0.17 episodes per 100,000 person-years.38 ^,​ 39 ^,​ 40 It occurs in 0.6 to 10% of all cases of PA, has a discrete predominance in males, and frequently occurs in the fifth or sixth decade of life.38 ^,​ 39 ^,​ 40 It is typically characterized by sudden severe headache, visual loss, ophthalmoplegia, and altered mental status. Anterior pituitary hormone dysfunction is present in about 80% of patients at initial presentation.38 ^,​ 39 ^,​ 40 The most critical deficiency is ACTH, observed in about 70% of cases, which may manifest with hypotension and hyponatremia. An acute hemorrhagic component can be visualized on CT scan (Fig. 39.5), whereas MRI is most beneficial for subacute and chronic stages of apoplexy. Interestingly, mucosal thickening is often seen within the sphenoid sinus adjacent to the apoplectic tumor. Peripheral enhancement is typically seen in most cases; rarely, an empty sella may be present. Factors predisposing toward the development of pituitary apoplexy include vascular flux alterations during surgery, radiotherapy, and postspinal anesthesia; acute increase in blood flow during physical activity and systemic hypertension; dynamic stimulatory tests of pituitary gland during provocative tests; hypoglycemia with insulin administration; coagulation disturbances with the use of anticoagulation and presence of thrombocytopenia; pregnancy; sickle cell anemia; estrogen replacement; lymphocytic leukemia; head trauma; and cessation of dopamine agonist therapy.38 ^,​ 39 ^,​ 40 Occasionally, pituitary apoplexy may occur in microadenomas.42

39.5.1 Conservative Management

Because microincidentalomas grow much more slowly than macroincidentalomas do, microincidentalomas are usually monitored using repeat imaging to ascertain the growth rate of the lesion. Nonfunctional microincidentalomas of < 5 mm size require no surveillance, and those ≥ 5 mm do not require surgical resection but rather require close radiological surveillance at 6 months and subsequently at 2 years.27 Conversely, macroincidentalomas demonstrate tumor progression in 20 to 24% and 34 to 40% of patients at 4- and 8-year follow-up, respectively; thus they are followed more cautiously and the threshold for active intervention is lower.27 Nonfunctioning macroincidentalomas situated remote from the optic apparatus are monitored with MRI along with complete hormonal profile (to look for anterior pituitary dysfunction) every year, then every 2 years.27 When the macroincidentaloma is in proximity to the optic apparatus and is managed conservatively using surveillance rather than surgery, MRI is recommended at 6 months with hormonal profile and ophthalmological evaluation. Subsequently, annual MRI is advised along with hormonal and visual assessment every 6 months.27

If there is a tumor remnant after initial surgical decompression of a symptomatic NFPA, two options are available: simple surveillance or adjuvant therapy. The appropriate treatment decision has to be made in agreement with the patient and involves a multidisciplinary approach. The factors weighed in the decision-making process are the clinical profile of the patient, including age, comorbid status, and ability to undergo prolonged surveillance; tumor morphology, including size, pattern of extension, relation to the optic apparatus, and evidence of cavernous sinus invasion; pathological findings, including WHO grading, IHC, Ki-67 labeling index, and p53 expression; remnant progression; presence or absence of hypopituitarism; and availability of, and experience with, adjuvant therapeutic options in the treating center. Often in such cases, unless an elevated growth potential is reflected by the tumor, postponing radiotherapy is usually recommended until radiological progression is manifested, because the efficacy is comparable regardless of whether treatment is immediate or postponed.28

39.5.2 Surgery

The surgical success rate is dependent on patient age; tumor size, pattern of extension, WHO grade and precise ultrastructural morphology, degree of invasiveness, and proliferation potential; the magnitude of hormonal hypersecretion (for functional tumors); and the experience level of the surgeon.7

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