15 minute read
Workup for Incidental Pituitary Adenoma in Primary Care Setting
Pituitary gland tumors are often found incidentally on imaging studies or during workup for abnormal endocrine hormone levels.
Approximately 65% of pituitary adenomas are functioning tumors.
A35-year-old woman is seen for evaluation of an incidental pituitary macroadenoma. Her medical history is signi cant for hypertension, diabetes, hyperlipidemia, polycystic ovary syndrome, and obesity. She initially presented to the emergency department (ED) a week ago after an episode of right visual eld changes that she described as waviness in her right eye and right hemibody sensory changes without motor de cits. While in the ED, she underwent a full workup for possible stroke, which was negative. Magnetic resonance imaging (MRI) of her brain without contrast revealed a 12-mm pituitary lesion; a repeat MRI with contrast was then ordered (Figure, page 12). No serum hormonal panel was available for review from ED records. Upon further questioning of her medical history, the patient notes that a few years ago she was attempting to become pregnant and was evaluated by her gynecologist for amenorrhea. At that time, she reportedly completed an endocrine laboratory workup that showed a slightly elevated prolactin level between 30 and 40 ng/mL ( normal level in nonpregnant women, <30 ng/mL). Per the patient, the minimal elevation was not enough to concern the gynecologist and no MRI was ordered at that time. Her gynecologist recommended that she lose weight. Her menses returned to normal with weight loss. With a history of disrupted menstrual cycles, infertility, and patient-reported elevated prolactin level, there is high suspicion for endocrine disruption.
FIGURE 1. Magnetic resonance imaging of the case patient. Left image: sagittal view. Right image: coronal view with contrast.
A complete pituitary panel is ordered to examine the current hormone level considering the recent MRI findings. This revealed a prolactin of 33.7 ng/mL; all other hormone levels were within normal limits.
Because the patient reports multiple episodes of visual disturbances and the size of the pituitary adenoma on MRI, a neuroophthalmology referral is initiated for testing and to determine if the pituitary macroadenoma is causing mass effect and compressing the optic nerve. The neuro-ophthalmologist found she had no visual field defect from her adenoma on testing and believed that her visual disturbances were probably migraine in nature.
Discussion
Pituitary gland tumors are usually found incidentally on imaging studies obtained for other reasons or in workup of patients with abnormal endocrine hormone levels (both decreased and increased levels) or with symptoms of mass effect from the lesions.1 These tumors are typically benign in nature; cases with malignancy are extremely rare.1 The exact pathophysiology of pituitary adenomas remains unknown but is thought to be linked to heredity, hormonal influences, and genetic mutations.1
Pituitary tumors are commonly found in adults between the ages of 35 and 60 years.2,3 The estimated prevalence of pituitary adenomas varies widely by study and findings are typically based on autopsy and radiology data. Surveillance, Epidemiology, and End Results (SEER) Program data from 2004 to 2018 show an incidence rate of pituitary adenomas and pituitary incidentalomas of 4.28 ± 0.04 and 1.53 ± 0.02 per 100,000 population.4 Pituitary tumors have been found in 14.4% of unselected autopsy cases and 22.5% of radiology tests.1
The SEER data suggest that incidence rates are similar among women and men but are higher among women in early life and higher among men in later life.5 Rates of prolactinomas (prolactin-secreting tumors) and corticotropinomas (adrenocorticotropic hormone-secreting tumors; Cushing disease) are higher in women than men.6
Earlier SEER data showed a significantly higher incidence of pituitary adenomas in Black individuals compared with other racial/ethnic groups; several factors may account for this discrepancy such as the higher stroke rate in this population, which leads to a greater likelihood for brain imaging that detects incident pituitary tumors.5
Incidental findings of pituitary adenoma may be found during workup related to hormonal dysfunction (amenorrhea, galactorrhea, fertility disorders, sexual dysfunction), noticeable vision change, new-onset headaches, or imaging performed for other diagnostic purposes.7
Pituitary Types
Pituitary tumor types are differentiated by location, size, and functional status. Pituitary tumors commonly arise from the anterior portion of the gland (adenohypophysis) and rarely from the posterior portion (neurohypophysis).2 Both adenohypophyseal and neurohypophyseal tumors are commonly benign and slow-growing.1 Malignant pituitary tumors account for less than 1% of pituitary lesions and are usually metastases from breast and lung cancers.3 Adenohypophyseal carcinoma is rare, with less than 140 reported cases.2
Pituitary tumors are categorized by the size1,2: • Microadenomas (<10 mm) • Macroadenomas (>10 mm to 40 mm) • Giant adenomas (>40 mm)
Pituitary adenomas are further classified as functioning (hormone-secreting) or nonfunctioning (nonsecreting).1,6 If
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the adenoma is functioning, hormone levels will be found in excess. If the levels are within normal limits, a nonfunctioning pituitary adenoma is suspected.
Functioning Tumors Approximately 65% of all pituitary adenomas are functioning tumors.2 Functioning pituitary adenomas present in various ways depending on which hormone is involved and the level of hormone secretion. Prolactinomas are the most common type of functioning adenomas followed by growth hormone-secreting and adrenocorticotropic hormonesecreting pituitary tumors. Adenomas secreting thyrotropin and follicle-stimulating hormone are less commonly found.2 Clinical features of functional pituitary adenomas are outlined in Table 1. 2,8
Nonfunctioning Tumors Approximately 20% to 30% of pituitary adenomas are nonfunctional.3 These tumors may go undiagnosed for years until the mass of the tumor starts to affect surrounding structures and cause secondary symptoms such as compression of the optic chiasm resulting in vision impairment.
Nonfunctioning pituitary adenomas and prolactinomas (functioning) are the 2 most common types of pituitary adenomas.2,3 The consulting clinician must understand the difference in pathology of these 2 types of lesions, what diagnostic test to order, how to interpret the test results, and which specialty to refer the patient to based on the initial workup findings.
Initial Workup
Proper baseline workup should be initiated before referring patients with incidental pituitary adenoma to a specialist. The initial workup includes imaging, blood work to determine if the pituitary adenoma is causing hormonal dysfunction, and neuro-ophthalmology referral for visual field testing to determine if the optic nerve/chiasm is affected.
Imaging The most accurate diagnostic modality of pituitary gland pathology is MRI with and without contrast. The MRI
TABLE 1. Clinical Features and Laboratory Findings of Functioning Pituitary Adenomas2,8
Adenoma Type Percentage of Functioning Pituitary Adenomas, % Clinical Features Laboratory Findings
Prolactin-secreting 48
Growth hormone-secreting 10
Adrenocorticotropic hormone-secreting 6 • Moon face appearance • Buffalo hump • Skin abnormalities: –Abdominal purple striae –Ecchymosis –Thinning of the skin • Proximal muscle weakness with distal strength intact • Normal to elevated ACTH level • Hyperglycemia • Loss of diurnal variation in cortisol levels • Elevated 24-hour urine free cortisol
Thyrotropin-secreting 1 • Amenorrhea • Erectile dysfunction • Loss of libido • Galactorrhea • Gynecomastia • Fertility issues • Prolactin >150 ng/mL
• Enlarged, protruding jaw • Enlarged frontal bones • Enlarged and swollen hands and feet • Metabolic disorders • Facial disfigurement • Musculoskeletal disabilities • Respiratory and cardiovascular dysfunction • In acromegaly, GH >10 ng/mL • Elevated IGF-1
• Enlarged thyroid • Hypothyroidism • Headache • Loss of vision • Galactorrhea • FT3 >14 pmol/L • Thyrotropin >3 mIU/L • Elevated alpha-GSU/thyrotropin molar ratio
ACTH, adrenocorticotropic hormone; FT3, tri-iodothyronine, free; GH, growth hormone; GSU, glycoprotein subunit; IGF-1, insulinlike growth factor 1
should focus on the hypothalamic-pituitary area and include contrasted imaging to evaluate the soft tissue within the intracranial structure.9 The coronal and sagittal views are the best to display the pituitary gland width and height and identify abnormalities.9 The MRI provides a detailed evaluation of the pituitary gland related to adjacent structures within the skull, which helps to detect microalterations of the pituitary gland.10 If a pituitary adenoma is an incidental finding on another imaging modality (such as a computed tomography scan or MRI without contrast), an MRI with and without contrast that focuses on the pituitary gland should be obtained.
Pituitary Laboratory Panel A complete pituitary panel workup should be obtained including prolactin, thyrotropin, free thyroxine, cortisol (fasting), adrenocorticotropic hormone, insulinlike growth factor 1, growth hormone, follicle-stimulating hormone, luteinizing hormone, estradiol in women, and total testosterone in males.1 Tests should be completed in the morning while fasting for the most accurate results. For instance, normally cortisol levels drop during fasting unless there is an abnormality. Table 2 shows normal laboratory ranges for a complete pituitary panel.
Serum prolactin levels can slightly increase in response to changes in sleep, meals, and exercise; emotional distress; psychiatric medications; and oral estrogens. If the initial prolactin level is borderline high (21-40 ng/mL), the test should be repeated. Normal levels are higher in women than in men. Microadenomas may cause slight elevations in prolactin level (ie, <200 ng/mL), while macroadenomas are likely to cause greater elevations (ie, >200 ng/mL).1 Patients with giant prolactinomas typically present with prolactin levels ranging from 1000 ng/mL to 100,000 ng/mL.11
Perimetry Pituitary adenomas may cause ophthalmologic manifestations ranging from impaired visual field to diplopia because of upward displacement of the optic chiasm. The optic chiasm is located above the pituitary gland and a pituitary tumor that grows superiorly can cause compression in this area.12 Optic chiasm compression from a pituitary adenoma commonly causes bitemporal hemianopsia.2 If the tumor volume is promptly reduced by surgical resection or medication (in the case of prolactinomas), initial vision changes resulting from compression may be reversible.12
Baseline and routine follow-up perimetry are important in patients with pituitary adenoma, as symptoms of optic chiasm compression may go unnoticed by patients as visual field deficits often develop gradually. Also, post-treatment perimetry assessments can be used to compare the initial testing to evaluate reversible visual field deficits. It is recommended that patients
TABLE 2. Normal Values for Pituitary Panela
Pituitary Test Normal Value
Thyrotropin 0.5-5.0 mIU/L
Thyroxine, free 0.7-1.9 ng/dL
Cortisol (fasting) Adults 8 AM (7-9 AM) specimen: 4.0-22.0 µg/dL Adults 4 PM (3-5 PM) specimen: 3.0-17.0 µg/dL
Adrenocorticoid hormone <54 ng/L
IGF-1 Age ng/mL 18-19.9 years .................... 108-548 20-24.9 years ..................... 83-456 25-29.9 years ..................... 63-373 30-39.9 years ..................... 53-331 40-49.9 years ..................... 52-328 50-59.9 years ..................... 50-317 60-69.9 years ..................... 41-279 70-79.9 years ..................... 34-245 ≥80 years......................... 34-246 Z-Score (men): -2.0 to +2.0 SD Z-Score (women): -2.0 to +2.0 SD
Growth hormone Adults: ≤7.1 ng/mL
Prolactin Men: <25 ng/mL Women: • Nonpregnant: <30 ng/mL • Pregnant: 10-400 ng/mL
Follicle-stimulating hormone Men: 1.6-8.0 mIU/mL Women: • Follicular phase: 2.5-10.2 mIU/mL • Mid-cycle peak: 3.1-17.7 mIU/mL • Luteal phase: 1.5-9.1 mIU/mL • Postmenopausal: 23.0-116.3 mIU/mL
Luteinizing hormone Men: • Age 18-59: 1.5-9.3 mIU/mL • Age ≥60: 1.6-15.2 mIU/mL Women: • Follicular phase: 1.9-12.5 mIU/mL • Mid-cycle peak: 8.7-76.3 mIU/mL • Luteal phase: 0.5-16.9 mIU/mL • Postmenopausal: 10.0-54.7 mIU/mL
Estradiol Men: ≤29 pg/mL Women: • Follicular stage: 39-375 pg/mL • Mid-cycle stage: 94-762 pg/mL • Luteal stage: 48-440 pg/mL • Postmenopausal: ≤10 pg/mL
Testosterone Men: 250-827 ng/dL
IGF-1, insulinlike growth factor 1 a Values are from a single laboratory; values may vary per institution and/or laboratory.
with pituitary adenomas (both function and nonfunctiong) receive neuro-ophthalmologic evaluations twice a year to ensure no visual changes have occurred.12
Referral to a Specialist
Management of pituitary adenomas requires a multidisciplinary team of specialists including endocrinologists, neurosurgeons, and neuro-ophthalmologists. The type of adenoma governs which specialist patients with incidental adenoma should see rst.
Patients with functioning pituitary adenomas should be referred to an endocrinologist before a neurosurgeon. The most prevalent functioning adenomas, prolactinoma, are initially treated with dopamine agonist medications.1,6 A patient with prolactinoma would only need to see a neurosurgeon if they have a macroadenoma that is not responsive or only partially responsive to dopamine agonists therapy or is causing vision de cits related to compression of the optic chiasm.2
Patients with nonfunctioning pituitary adenomas should rst be referred to a neurosurgeon to discuss surgical options vs observation. The recommended treatment for patients with nonfunctioning adenomas and clinical features of mass e ect (ie, visual de cits) is surgery.1,6 If the patient is asymptomatic with no signs of visual eld de cits, the neurosurgery team may recommend continued surveillance with serial imaging and serial perimetry screenings.12
The patient in the case was found to have a nonfunctioning pituitary adenoma (prolactin was 33.7 ng/mL). Neuroophthalmology did not nd any visual eld defect upon initial assessment; the patient decided to continue observation with serial imaging (MRI) and serial neuro-ophthalmology assessments. Serial imaging with brain MRI revealed slow progression of the pituitary macroadenoma (12 mm initially; 13 mm 6 months later; and 14 mm 1 year from initial MRI ndings). Although the patient still did not have any visual eld defects per the neuro-ophthalmology reassessments, the documented growth on MRI over a short period of time was enough to make the patient more amenable to surgical resection. The patient underwent trans-sphenoidal resection of the pituitary lesion approximately 16 months after discovery of the tumor.
Conclusion
A thorough workup including laboratory testing, imaging, and vision eld testing is the foundation of an e ective referral process for pituitary adenomas and guides which specialist is consulted rst. If patients are referred before initial workup is completed, delays in care, unnecessary specialty visits, and increased overall health care costs may occur. ■
POLL POSITION
Approximately what percentage of all pituitary adenomas are functioning tumors?
■ 25%
■ 45%
■ 50%
■ 65% 25.23%
4.5% 58.56%
11.71%
For more polls, visit ClinicalAdvisor.com/Polls. Melissa Wasilenko, MSN, RN, is a registered nurse at Lyerly Neurosurgery in Jacksonville, Florida. She is currently pursuing a doctorate in nursing practice with a focus in family medicine at the University of North Florida in Jacksonville.
References
1. Russ S, Anastasopoulou C, Sha q I. Pituitary adenoma. 2021 Jul 18. In: StatPearls. StatPearls Publishing; 2022 Jan–. Updated July 18, 2021. 2. Greenberg MS. Tumors of non-neural origin. In: Handbook of Neurosurgery, 9th ed. Thieme Medical Publishers: 2019;1655-1755 3. Yeung M, Tahir F. The pathology of the pituitary, parathyroids, thyroid and adrenal glands. Surgery. 2020;38(12):747-757. 4. Watanabe G, Choi SY, Adamson DC. Pituitary incidentalomas in the United States: a national database estimate.World Neurosurg.2021:S1878-8750(21)01780-0. 5. McDowell BD, Wallace RB, Carnahan RM, Chrischilles EA, Lynch CF, Schlechte JA. Demographic differences in incidence for pituitary adenoma. Pituitary. 2011;14(1):23-30. 6. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516-524. 7. Yao S, Lin P, Vera M, et al. Hormone levels are related to functional compensation in prolactinomas: a resting-state fMRI study. J Neurol Sci. 2020;411:116720. 8. Beck-Peccoz P, Persani L, Lania A. Thyrotropin-secreting pituitary adenoma. In: Feingold KR, Anawalt B, Boyce A, et al, eds Endotext. MDText.com, Inc.; 2019. 9. Yadav P, Singhal S, Chauhan S, Harit S. MRI evaluation of size and shape of normal pituitary gland: age and sex related changes. J Clin Diagnostic Research. 2017;11(12):1-4. 10. Varrassi M, Cobianchi Bellisari F, Bruno F, et al. High-resolution magnetic resonance imaging at 3T of pituitary gland: advantages and pitfalls. Gland Surg. 2019;8(Suppl 3):S208-S215. 11. Shimon I. Giant prolactinomas. Neuroendocrinology. 2019;109(1):51-56. 12. Vié AL, Raverot G. Modern neuro-ophthalmological evaluation of patients with pituitary disorders. Best Pract Res Clin Endocrinol Metab. 2019;33(2):101279.
Conference Roundup
American Academy of Allergy, Asthma & Immunology (AAAAI) 2022 Annual Meeting
February 25 to 28, 2022 Phoenix, Arizona
GUT MICROBIOTA, DIET, AND ALLERGIC ASTHMA PHENOTYPES IN CHILDREN
Metabolic dysfunction/gut microbiota associated with atopy and asthma in children are related to the consumption of processed food, according to study findings presented at the AAAAI 2022 Annual Meeting. The study also identified specific diet-microbe interactions that potentially contribute to disease severity.
Researchers sought to determine whether gut microbes and their by-products interact with dietary exposures and influence allergy and asthma phenotypes. The trial included 345 children who were classified into 6 respiratory phenotypes based on lung function, wheeze, and atopic disease trajectories. The researchers then assessed these children for features of the gut microbiome (utilizing 16S ribosomal ribonucleic acid [rRNA] and shotgun metagenomic sequencing) and diet (using the Block Food Frequency Questionnaire).
Researchers found 4 gut microbiota structures that were significantly associated with respiratory phenotype (P =.04), socioeconomic status (P =.04), site (P =.005), and a range of measurements of atopy (all P <.04). In children with allergic asthma and low lung function, a bacterial network dominated by Prevotella showed significantly reduced abundance. Dietary exposures were also associated with respiratory phenotypes (analysis of variance P =.03). Children less likely to have severe asthma were those with a low abundance of gut networks of Christenellaceae, Methanobacteriales, and Clostridia and whose diets were rich in whole foods (interaction P =.03).
“Our data indicate that the gut microbiota remains associated to phenotypes of atopic asthma in later childhood and also [identify] specific diet-microbe interactions that may modulate or contribute to disease severity,” the researchers concluded.
Specific diet-microbe interactions may contribute to asthma severity in children.
REAL WORLD STUDY EVALUATES ORAL PEANUT IMMUNOTHERAPY
Children who underwent real-world peanut oral immunotherapy (P-OIT) at a large tertiary referral academic center tolerated the treatment well, but older children required more dose reductions when being desensitized to high-dose maintenance therapy, according to research presented at the AAAAI 2022 Annual Meeting.
Investigators conducted a real-world, retrospective review of patients who underwent P-OIT at an academic tertiary referral center between 2018 and 2020. All participants were sensitized to low-dose (ie, 300-500 mg) or highdose (ie, 1500-2000 mg) daily peanut protein (PP). Measures of effectiveness included the following: (1) proportion of patients who attained maintenance; and (2) tolerance of a 6000-mg PP challenge following 12 months of high-dose maintenance. All patients were stratified into 2 groups based on age: a younger group of children 72 months of age and younger (preschool-aged) and an older group of children (older than 72 months of age).
A total of 85 patients underwent P-OIT, with 45 in the younger group and 40 in the older group. Overall, 17 patients discontinued the study prior to maintenance therapy and 11 withdrew because of adverse reactions. A maintenance dose was achieved in 80.0% (68 of 85) of the participants, and 69.4% (59 of 85) of patients achieved high-dose maintenance regardless of age (younger group: 68.9% [31 of 45] vs older group: 72.5% [28 of 40]).
Six patients in the younger group receiving high-dose maintenance therapy
