Prolactinoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

Prolactinoma is the most common type of pituitary adenoma. Prolactinoma may occur in approximately 30% of multiple endocrine neoplasia type 1 patients. It may also occur with Carney complex or McCune-Albright syndrome. Prolactinoma is also associated with various familial syndromes for example MEN1 syndrome. There have been familial cases of prolactinoma unrelated to MEN 1 syndrome as well. On gross pathology, prolactinoma is divided on the basis of size into microprolactinoma and macroprolactinoma. On histological analysis, prolactinoma may be divided into sparsely granulated and densely granulated.

• Prolactinoma arises from lactotrophs, which are secretory cells of anterior pituitary lobe and are normally involved in secretion of prolactin hormone.
• The increase in amount of lactotrophs produces excess amount of prolactin causing hyperprolactinemia.
• Hyperprolactinemia causes symptoms such as amenorrhoea/oligomenorrhoea and galactorrhea in females and impotence in males. Hyperprolactinemia also causes infertility, decreased libido and osteoporosis in both sexes.
• As prolactinoma increase in size, it causes mass effect. The most common mass effect include headache and defect in peripheral vision (bitemporal hemianopsia).

Prolactinoma may be associated with:^[1]

• Multiple endocrine neoplasia type 1 (MEN 1)

• Carney complex
• McCune-Albright Syndrome

• Prolactinoma are monoclonal in nature. This suggests that the somatic cell mutation responsible for the development of prolactionoma, occurs before clonal expansion of lactotrophs.^[2]

• One gene involved in the pathogenesis of prolactinoma is the pituitary tumor transforming gene-1 (PTTG-1).^[3][4]
  • The PTTG-1 gene is related to various endocrine and non-endocrine tumors such as:
    • Endocrine related tumors: pituitary, thyroid, breast, ovarian, and uterine tumors.
    • Non-endocrine related tumors: central nervous system, pulmonary, and gastrointestinal tumors.
  • Prolactinomas with a higher expression of the PTTG-1 gene tend to be more invasive.

• Many prolactinomas are related to multiple endocrine neoplasia type 1.^[5]
  • The MEN1 gene is located on 11q13.
  • The MEN1 gene is a tumor suppressor gene that follows the concept of ‘two-hit hypothesis,’ which implies that both alleles that code for a particular gene must be affected before an effect manifests.
  • The consequence of this mode of tumor development is that if one allele for the gene is damaged, the second can still produce the correct form of normal protein.
  • Affected individuals carry one altered copy of the MEN1 gene and the other copy is lost due to somatic mutation.

• A pituitary adenoma may be part of a familial syndrome:^[6]

The gross pathology of prolactinoma is as follows:^[8]

• Microprolactinomas (<10mm size) are usually found in the lateral wing of the pituitary gland. They are most often surrounded by well defined pseudocapsules composed of reticulin.
• Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause sellar expansion while others invade the base of the skull.
• About 50% of all prolactinoma grossly invade surrounding structures.

• Prolactinoma are divded into two types based on microscopy:^[8]
• Sparsely granulated variant
  • This is common type of variant.
  • This contains chromophobic cells.
• Densely granulated variant
  • This is a rare varaint.
  • This contains acidophilic cells.

Note: There is no clinical, biological and prognostic difference between the two variants.

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