Prolactin-secreting adenomas or prolactinomas constitute the largest group of pituitary adenomas in an autopsy series. They are responsible for approximately 27% of pituitary tumors. In the advent of medical therapy, less than 90% of prolactinomas are surgically treated. Normal serum prolactin levels are less than 20 ng/mL. Prolactinomas and other conditions that lead to hyperprolactinomas result in significant symptoms. Table 21-1 lists pathological causes of hyperprolactinemia other than prolactinomas. Size does generally correlate with level of prolactin; however, levels less than 150 ng/mL reflect more of compression of the pituitary stalk particularly when combined with secondary hypogonadism. Treatment is currently reserved for mainly: personal choice, intolerance of medication at an effective dose, wish for pregnancy, inadequate response to medication, primary amenorrhea, prolactin value of less than 200 μg/L, male sex, and extrasellar extension. Additionally in men, infertility, decreased libido, and impotence are reasons for surgery.
Surgery is performed predominantly by the transsphenoidal approach, with extremely low morbidity (2.2%) and mortality (0.5%). With the advent of medical therapy, however, careful screening of patients needs to be undertaken to reduce this risk even further.
Occurrence varies with age and sex. Females between the ages of 20 and 50 years have the highest incidence. Prolactinomas are classified by size and also location (intrasellar, extrasellar extension). Microprolactinomas are equal to or less than 10 mm in diameter. Macroprolactinomas on the other hand are greater than 10 mm. Another class of macroadenomas known as giant macroadenomas are equal to or greater than 40 mm. Macroprolactinomas with increasing size tend to exhibit more mass effect on surrounding structures such as optic chiasm compression, leading to visual defects—most commonly bitemporal hemianopsia and decreased visual acuity. Headaches are also very common. With large macroadenomas, cavernous sinus compression with facial pain, diplopia, and anisocoria have been documented.
Magnetic resonance imaging (MRI) is the imaging modality of choice for pituitary masses. This provides an opportunity to the physician for not only defining the mass dimensions and location but also allows operative planning with respect to identifying vasculature, such as the cavernous sinus and sellar region of the carotid arteries.
The tumors on T1-weighted scans appear as low intensity localized lesions, whereas they are high intensity on T2-weighted scans. Most predominantly for surgical planning, T1-weighted contrasted image is used. This allows for contrast enhancement of tumors of the sella. Nevertheless, a crucial factor in evaluating an intracellular pituitary tumor is to closely correlate clinical and radiological findings.
Pathology (See Figures 21-1 and 21-2 )
Under electron microscopy, prolactinoma cells mostly appear sparsely granulated with notably large nuclei and also dense nucleoli. There is an abundant rough endoplasmic reticulum and Golgi apparatus. Another notable feature is that secretory granules are extruded into the extracellular space. Extrusion, and not the size of the granules, or development of Golgi apparatus, correlates with increased endocrine activity. Other features prevalent in prolactinomas are calcifications.
Two postulates on the initiating circumstances leading to the development of prolactinomas include (1) Intrinsic pituitary abnormalities and (2) Hypothalamic dysfunction. The two postulates have had numerous papers in support or against. In postulates regarding hypothalamic dysfunction, excessive prolactin releasing factors and/or lack of adequate secretion of prolactin inhibitory factors such as dopamine have been considered. Sadly, at this time, no definite evidence exists.
With respect to prolactinomas developing as a result of intrinsic pituitary dysfunction, several papers do report resistance to dopamine inhibition. This is further supported by the fact that after resection, with the preservation of a normal pituitary gland, there is return of function and in most cases normal levels of prolactin. The issue of recurrence is believed to be indicative of retained tumor fragments and not by hypothalamic stimulation. Mention must be made of the fact that resistance is partial and in most cases based on the therapeutic efficacy of dopaminergic agonists, such as bromocriptine and cabergoline, in decreasing PRL release and tumor size. Macroadenomas are far more subject to aggressive, invasive, and recurrent local growth, very often preventing complete removal. Based on multiple series of microadenomas that have been observed for possible evolution into macroadenomas, it can be inferred that 3% to 7% of microprolactinomas will eventually progress to be macroprolactinomas.
Another question of origin of prolactinomas is whether they are polyclonal or monoclonal. Evidence currently supports the monoclonal theory of tumor generation. For tumors to be polyclonal and hence arise as result of hypothalamic influence, there should be multiple clones of cells when examined after tumor formation. Monoclonal cells would be a result of spontaneous mutation in one cell. Monoclonal nature of prolactinomas from the previously mentioned study of Herman et al did, however, indicate “a facilitory role for the hypothalamus in pituitary tumorigenesis, perhaps by inducing clonal expansion of a genomically altered cell”
Two decades after Forbes, Henneman, Grisworld et al described the relationship between the amenorrhea-galactorrhea syndrome and the presence of pituitary tumors, prolactin was isolated and characterized as the pathophysiological hormone involved in the previously cited endocrinological outcome. Table 21-2 lists the endocrinological outcomes of hyperprolactinemia. Pulsatile secretory activity of gonadotropin-releasing hormone (GnRH) is grossly affected, leading to hypogonadism as a net effect of hyperprolactinemia.
|Premenopausal Women||Postmenopausal Women||Male|
|Secondary amenorrhea||Headache/visual defects||Headache /visual deficits|
|Infertility (regular menses)|
|Headache/ visual defects|
Before any therapy for hyperprolactinemia, confirmation of elevated serum PRL must be made. Other than pregnancy or postpartum lactation, serum PRL levels are normally less than 20 ng/mL. In addition to the clinical symptoms described in Table 21-2 , a high serum prolactin level greater than 200 ng/ml may be diagnostic. However in our series, a single laboratory value may not be confirmatory due to stalk effect. In addition, serum levels of greater than 1000 ng/mL in practice have been consistent with invasive tumors.
Bitemporal hemianopsia is the most common visual defect noted as a result of direct impingement of the optic chiasm by the expanding mass. Other cranial nerve dysfunction can occur based on location and extension of a tumor. With secreting tumors, however, the incidence of chiasmal compression is much reduced as the endocrine consequence (including hypopituitarism) to such tumors often is apparent before enlarged growth.
The endocrine dysfunction in men may go unnoticed for months to years. Erroneous treatment of medical conditions leading to impotence or infertility may delay accurate diagnosis of a large pituitary prolactinoma in males with resultant hypogonadism.
One other factor about clinical presentation of prolactinomas relates to the predominance of macroadenomas in men. Local effects of tumor, as first presenting sign, occurs in about one third of men. One postulate currently under investigation is the possibility of differential effects of tumor growth factors on both sexes. Another is the likelihood of differential sensitivity to hyperprolactinemia, with men requiring higher amounts to stimulate endocrine suppression. This, however, is strongly refuted in several series showing improved endocrine function after treating mild hyperprolactinemia in men.
Options for Patients with Prolactinomas
When considering treatment for the patient with PRL, a multidisciplinary approach should be used to first evaluate and establish diagnosis with emphasis on anatomical (invasiveness, potential for resection) and endocrine considerations. A prudent and worthwhile approach is the involvement of an endocrinologist and neurosurgeon in patient care before beginning therapy for especially easily respectable tumors. Goals should be focused as outlined in Kaye and Laws in
Restoration of normal endocrine function and reverse pathology
Elimination of mass effect and restoration of neurological function
Elimination or minimizing of the possibility of tumor recurrence
Obtaining a definitive histological diagnosis
With the previous goals in mind, the team, including the patient, then makes a concrete plan of attack. At this point, 90% of tumors are amenable to medical therapy and often this is the primary choice of action.
Medical Therapy for Prolactinomas
Medical therapy as reiterated previously is the first line therapy for prolactinomas. Bromocriptine was the first dopaminergic agent used. Currently other agents include cabergoline and pergolide. The D 2 receptors of lactotroph cells are activated resulting in the cellular response involved in suppression of prolactin levels through decreased activation of adenyl cyclase, cAMP, and intracellular calcium levels. Tindall described the secretory suppression at the cellular level (retraction and involution of rough endoplastic reticulum and Golgi bodies) in the administration of dopamine agonist.
The subject of tumor perivascular, interstitial fibrosis and calcification from long-term use of dopamine agonists has long been debated since initial reports from Landolt. A few papers mention subsequent surgical resection being difficult with an increased complication rate.
Currently, the dopamine agonists used include bromocriptine and dopamine related substances (pergolide mesylate, Lisuride, cabergoline, and the nonergot agent, quinagolide). The effectiveness of these agents used as first-line therapy has been extensively explored for all age groups and genders.
The need for surgery is primarily (among other reasons: Table 21-3 ) indicated because of a lack of response or intolerance of medications. As documented and also from our experience at the University of Virginia, Charlottesville, response varies in continuum. This can be from complete resolution of symptoms, shrinkage, and normalization of prolactin levels through partial response to one of the previously mentioned three to lack of response and even progression of disease.