Pituitary Tumors—Misdiagnosed, Overtreated, Inadequately Studied

Review study raised questions about identification and treatment of rare pituitary adenomas. For now, individualized management should remain the standard of care.

With Maria Fleseriu, M.D, and Marcello D. Bronstein, MD, PhD

Pituitary tumors, the fourth most common type of intracranial cancer, are typically slow-growing and non-cancerous—until they are not.1 Rare pituitary tumors have remained under the radar of TSH-secreting pituitary adenomas.

This form of endocrine growth has remained so understudied that there isn’t yet agreement on what constitutes remission, nor are the factors used to diagnose these adenomas, including symptoms, radiological signs of disease, abnormal thyroid hormone levels, do not predict long-term remission.

Testing for TSH is a first step in identifying a rare pituitary tumor.

A Closer Look at What Is Known About Rare Pituitary Tumors

Fortunately, advances in the pathology bode well as to the ability to detect and identify these once hidden pituitary tumors. In a review of the literature,a research team analyzed data from 23 studies, published between 1990 and 2018, to assess the evidence on tumor size, invasiveness, outcomes, and post-operative treatment of these rare pituitary tumors. 

In all, there were 536 patients of which 52% were women, and the mean age of the patients was 45 years.3 The authors noted the following:

  • 67% had clinical hyperthyroidism
  • 90% had biochemical hyperthyroidism.
  • 79.6% had the presence of macroadenomas
  • 22% had microadenomas (which was double that reported in a 2000 report (P = .04)

The authors reported that two-thirds of the patients had clinical hyperthyroidism, while 90% had confirmed biochemical hyperthyroidism.3 “We concluded that one-third of these patients had no signs or symptoms of hyperthyroidism whilst 10% of patients may have expressed no modification of their thyroid profile and were diagnosed essentially by immunohistochemistry,” the authors wrote, “as clinical and radiological features are not specific.”

Other non-TSH pituitary hormones, including growth hormone and prolactin, were present in more than 40% of patients.3

A reported 79% of the patients were determined to have macroadenomas with 44% of this cohort experiencing extracellular extension and 30% of them diagnosed with cavernous sinus invasion.

Biochemical remission after surgery was 69.7%, and gross total resection was seen in 54% of these patients. Resection extent was much greater in the cases of microadenoma, and where there was cavernous sinus invasion, a lower rate of resection was common.

Two-thirds of the patients undergoing surgery achieved biochemical remission following radiation therapy, while the rate of remission was slightly higher at 75% in patients undergoing additional medical treatment. Overall, the authors reported a combined remission rate of 67% achieved in this patient population.3

Gains In Knowledge, Limits in Management of Rare Tumors

While the data in the review offers some very interesting insights, there are some missing pieces that need clarification, said Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland.

“This study, being a systematic search and meta-analysis of surgical series, summarized the evidence about the outcomes and treatment postoperatively, thus data on primary medical therapy, which is sometimes used for these tumors is missing,” and would be helpful for clinical guidance, said Dr. Fleseriu.

In addition, in most of the studies evaluated in this research review,the patients were treated at specialized centers so the high rate of success in these patients is likely attributable to the level of care, she tells EndocrineWeb. “Thus, the cure rate with surgery in the overall population for these rare pituitary tumors is actually much lower.”

The beauty of this review is how many cases of a very rare disease it brings into view, said

Marcello D. Bronstein, MD, PhD, professor of endocrinology, and chief of the Neuroendocrine Unit at the Hospital das Clinicas of the University of Sao Paulo.

The study also raised an important point about misdiagnosis,3 Dr. Bronstein told EndocrineWeb. Many patients with thyrotropin-secreting pituitary (TSP) adenomas—about a third of the cases in the study—were misdiagnosed as the much more prevalent primary hyperthyroidism in which TSH is undetectable, rather than a high or unexpected high normal TSH. These patients may then be “mistreated by thyroid surgery, radioiodine therapy, or thyroid blocker drugs, probably leading to increased TSP adenoma size and invasiveness.”

Another interesting fact that became clear from the data,3 Dr. Fleseriu said, is that although somatostatin receptor ligands (SRLs) were used more frequently than dopamine agonists (DAs) for TSH secreting tumors, in this meta-analysis, the remission rate was similar for both treatments. “Selection bias probably played a role in this finding and patients with milder disease were likely treated with DA and patients with severe disease with SRLs.”

Important Role for Primary Management of Pituitary Adenomas

While the authors did not make explicit statements about which treatments appeared more effective, the findings offered evidence in favor of primary medical treatment for bigger and more invasive TSP adenomas that were not expected to be adequately controlled by pituitary surgery, Dr. Bronstein said. “In fact, these SRLs targeted mainly SST2, the most prevalent somatostatin receptor subtype in TSP pituitary adenoma,” he said. 

In effect, since both somatostatin receptors and dopamine D2 receptor were found in TSA but the response usually is better with somatostatin receptor ligands, perhaps we may change the final sentence, Dr. Bronstein said. "Dopamine agonists such cabergoline may also be tried but usually they show less efficacy then SRL." 

Another takeaway from this study: Radiation after surgery, when combined with postoperative medical treatment, increased long term cure rates for most patients, although 14% had [pituitary] disease that persisted after treatment,3 Dr. Fleseriu said. However, there was little uniformity in the way remission and cure were defined across the various studies, with the authors indicating “no role for alpha subunit TSH molar ratio, TRH stimulation orT3 suppression tests as predictive factors for remission.”

The upshot, she told EndocrineWeb, is that the results of this review do not present any compelling reason to change the current approach to treatment—individualized management should remain the rule for TSH-secreting pituitary adenomas. “Most patients with a rare form of pituitary adenoma will require multimodal therapy and continual follow-up. Clearly, more research is needed to determine the best adjuvant therapy and if there is any role for increasing treatment with medication rather than referring for surgery in cases of small tumors.”

In the future, Dr. Bronstein said he would like to see more research related to TSP adenomas that focus on evaluating whether an endoscopic or microscopic approach is better for invasive macroadenomas. He would also like to see studies with longer follow-up of primary treatment with SRL, looking at efficacy, side effects, tachyphylaxis, and tumor shrinkage.

There is also a need for further study on the side effects of adjuvant radiation therapy, mainly related to hypopituitarism induction, and there is an ongoing need “to increase awareness and knowledge of this rare disease in the medical community to avoid inappropriate treatments,” he said.

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