Sparsely Granulated Corticotroph Pituitary Macroadenoma Presenting with Pituitary Apoplexy Resulting in Remission of Hypercortisolism

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Highlights

• We describe a rare case of a patient with a sparsely granulated corticotroph pituitary macroadenoma with pituitary apoplexy who underwent transsphenoidal resection resulting in remission of hypercortisolism.
• Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors.
• macroadenomas account for 7-23% of patients with pituitary corticotroph adenomas
• Sparsely granulated corticotroph tumors are associated with longer duration of Cushing disease prior to diagnosis, larger tumor size at diagnosis, decreased immediate remission rate, increased proliferative marker Ki-67 and increased recovery time of hypothalamic-pituitary-adrenal axis after surgery.
• Granulation pattern is an important clinicopathological distinction impacting the behavior and treatment outcomes of pituitary corticotroph adenomas

Abstract

Background

/Objective: Pituitary corticotroph macroadenomas, which account for 7% to 23% of corticotroph adenomas, rarely present with apoplexy. The objective of this report is to describe a patient with a sparsely granulated corticotroph tumor (SGCT) presenting with apoplexy and remission of hypercortisolism.

Case Report

A 33-year-old male presented via ambulance with sudden onset of severe headache and nausea/vomiting. Physical exam revealed bitemporal hemianopsia, diplopia from right-sided third cranial nerve palsy, abdominal striae, facial plethora, dorsal and supraclavicular fat pad. Magnetic resonance imaging (MRI) demonstrated a 3.2 cm mass arising from the sella turcica with hemorrhage compressing the optic chiasm, extension into the sphenoid sinus and cavernous sinus. Initial investigations revealed plasma cortisol of 64.08 mcg/dL (Reference Range (RR), 2.36 – 17.05). He underwent emergent transsphenoidal surgery. Pathology was diagnostic of SGCT. Post-operatively, cortisol was <1.8ug/dL (RR, 2.4 – 17), adrenocorticotropic hormone (ACTH) 36 pg/mL (RR, 0 – 81), thyroid stimulating hormone (TSH) 0.07 uIU/mL (RR, 0.36 – 3.74), free thyroxine 1 ng/dL (RR, 0.8 – 1.5), luteinizing hormone (LH) <1 mIU/mL (RR, 1 – 12), follicle stimulating hormone (FSH) 1 mIU/mL (RR, 1 – 12) and testosterone 28.8 ng/dL (RR, 219.2 – 905.6) with ongoing requirement for hydrocortisone, levothyroxine, testosterone replacement and continued follow-up.

Discussion

Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors. Sparsely granulated pattern is associated with larger tumor size and decreased remission rate after surgery.

Conclusion

This report illustrates a rare case of hypercortisolism remission due to apoplexy of a SGCT with subsequent central adrenal insufficiency, hypothyroidism and hypogonadism.

Keywords

pituitary apoplexy
pituitary macroadenoma
pituitary tumor
sparsely granulated corticotroph tumor
Cushing disease

Introduction

The incidence of Cushing Disease (CD) is estimated to be between 0.12 to 0.24 cases per 100,00 persons per year1,2. Of these, 7-23% are macroadenomas (>1 cm)345. Pituitary apoplexy is a potentially life-threatening endocrine and neurosurgical emergency which occurs due to infarction or hemorrhage in the pituitary gland. Apoplexy occurs most commonly in non-functioning macroadenomas with an estimated prevalence of 6.2 cases per 100,000 persons and incidence of 0.17 cases per 100,00 persons per year6. Corticotroph macroadenoma presenting with apoplexy is uncommon with only a handful of reports in the literature7. We present a case of a sparsely granulated corticotroph (SGCT) which presented with apoplexy leading to remission of hypercortisolism and subsequent central adrenal insufficiency.

Case Presentation

A 33-year-old male who was otherwise healthy and not on any medications presented to a community hospital with sudden and severe headache accompanied by hypotension, nausea, vomiting, bitemporal hemianopsia and diplopia. Computed Tomography (CT) scan of the brain demonstrated a hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica with extension into the right cavernous sinus and encasement of the right internal carotid arteries (Figure 1A). He was transferred to a tertiary care center for neurosurgical management with endocrinology consultation post-operatively.

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Figure 1. hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica on unenhanced CT (A); MRI demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogeneous mass on T1 (B) and T2-weighted imaging (C) showing small hyperintense areas in solid part of the sella mass with flattening of the optic chiasm, remodeling/dehiscence of the floor of the sella and extending into the right cavernous sinus with at least partial encasement of the ICA

In retrospect, he reported a 3-year history of ongoing symptoms of hypercortisolism including increased central obesity, dorsal and supraclavicular fat pad, facial plethora, abdominal purple striae, easy bruising, fatigue, decreased libido and erectile dysfunction. Notably, at the time of presentation he did not have a history of diabetes, hypertension, osteoporosis, fragility fractures or proximal muscle weakness. He fathered 2 children previously. His physical examination was significant for Cushingoid facies, facial plethora, dorsal and supraclavicular fat pads and central obesity with significant axillary and abdominal wide purple striae (Figure 2). Neurological examination revealed bitemporal hemianopsia, right third cranial nerve palsy with ptosis and impaired extraocular movement. The fourth and sixth cranial nerves were intact as was the rest of his neurological exam. These findings were corroborated by Ophthalmology.

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Figure 2. Representative images illustrating facial plethora (A); abdominal striae (B, C); supraclavicular fat pad (D); dorsal fat pad (E)

Initial laboratory data at time of presentation to the hospital included elevated plasma cortisol of 64.08ug/dL (RR, 2.36 – 17.05), ACTH was not drawn at the time of presentation, normal TSH 0.89 mIU/L (RR, 0.36 – 3.74), free thyroxine 0.91ng/dL (RR, 0.76 – 1.46), evidence of central hypogonadism with low total testosterone 28.8 ng/dL (RR, 219.2 – 905.6) and inappropriately normal luteinizing hormone (LH) 1mIU/mL (RR, 1 – 12) and follicle stimulating hormone (FSH) 3mIU/mL (RR, 1 – 12), low prolactin <1 ng/mL (RR, 3 – 20), and normal insulin growth factor – 1 (IGF–1) 179ng/mL (RR, 82 – 242).

A pituitary gland dedicated MRI was performed to further characterize the mass, which re-demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogenous mass at the sella turcica extending superiorly and flattening the optic chiasm, remodeling of the floor of the sella and bulging into the sphenoid sinus and extending laterally into the cavernous sinus with encasement of the right internal carotid artery (ICA). As per the radiologist’s diagnostic impression, this appearance was most in keeping with a pituitary macroadenoma with apoplexy (Figure 1B – C).

The patient underwent urgent TSS and decompression with no acute complications. Pathological examination of the pituitary adenoma showed features characteristic of sparsely granulated corticotroph pituitary neuroendocrine tumor (adenoma)8, with regional hemorrhage and tumor necrosis (apoplexy). The viable tumor exhibited a solid growth pattern (Figure 3A), t-box transcription factor (T-pit) nuclear immunolabeling (Figure 3B), diffuse cytoplasmic CAM5.2 (low molecular weight cytokeratin) immunolabeling (Figure 3C), and regional weak to moderate intense granular cytoplasmic ACTH immuno-staining (Figure 3D). The tumor was immuno-negative for: pituitary-specific positive transcription factor 1 (Pit-1) and steroidogenic factor 1 (SF-1) transcription factors, growth hormone, prolactin, TSH, FSH, LH, estrogen receptor-alpha, and alpha-subunit. Crooke hyalinization was not identified in an adjacent compressed fragment of non-adenomatous anterior pituitary tissue. Ki-67 immunolabeling showed a 1.5% proliferative index (11 of 726 nuclei).

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Figure 3. Hematoxylin phloxine saffron staining showing adenoma with solid growth pattern (A); immunohistochemical staining showing T-pit reactivity of tumor nuclei (B); diffuse cytoplasmic staining for cytokeratin CAM5.2 (C); and regional moderately intense granular cytoplasmic staining for ACTH (D). Scale bar = 20 μm

Post-operatively, he developed transient central diabetes insipidus requiring desmopressin but resolved on discharge. His postoperative cortisol was undetectable, ACTH 36 pg/mL (RR, 0 – 81), TSH 0.07 mIU/mL (RR, 0.36 – 3.74), free thyroxine 1 ng/dL (RR, 0.8 – 1.5), LH <1mIU/mL (RR, 1 – 12), FSH 1 mIU/mL (RR, 1 – 12) and testosterone 28.8 ng/dL (RR, 219.2 – 905.6) (Table 1 and Figure 4). One month later, he reported 15 pounds of weight loss and a 5-inch decrease in waist circumference. He also noted a reduction in the dorsal and supraclavicular fat pads, facial plethora, and Cushingoid facies as well as fading of the abdominal stretch marks. His visual field defects and right third cranial nerve palsy resolved on follow up with ophthalmology post-operatively. Repeat MRI six months post-operatively showed minor residual soft tissue along the floor of the sella. He is being followed by Neurosurgery, Ophthalmology, and Endocrinology for monitoring of disease recurrence, visual defects, and management of hypopituitarism.

Table 1. Pre- and post-operative hormonal panel

POD -1 POD 0 POD1 POD2 POD3 POD16 6 -9 months Comments
Cortisol(2.4 – 17 ug/dL) 64↓ 32↓ 11↓ <1.8↓ <1.8↓ 1.8↓ HC started POD3 post bloodwork
ACTH(0 – 81 pg/mL) 41↓ 36↓ 28↓ 13↓
TSH(0.36 – 3.74 uIU/mL) 0.89 0.43 0.12↓ 0.07↓ 0.05↓ 0.73
Thyroxine, free(0.8 – 1.5 ng/dL) 0.9 0.9 1.1 1 2.1↑ 1 Levothyroxine started POD4
LH(1 – 12 miU/mL) 1↓ <1↓ 1↓ 3
FSH(1 – 12 mIU/mL) 3↓ 1↓ 1↓ 3
Testosterone(219.2 – 905.6 ng/dL) 28.8↓ <20↓ 175.9↓ Testosterone replacement started as outpatient
Testosterone, free(160 – 699 pmol/L) <5.8↓ 137↓
IGF-1(82 – 242 ng/mL) 179 79
GH(fasting < 6 mIU/L) 4.5 <0.3
Prolactin(3 – 20 ng/mL) <1↓ <1↓

POD, postoperative day; HC, hydrocortisone; ACTH, adrenocorticotropic hormone; TSH, thyroid stimulating hormone; LH, luteinizing Hormone; FSH, follicle stimulating hormone; IGF-1, insulin like growth factor – 1; GH, growth hormone

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Figure 4. Trend of select pituitary hormonal panel with key clinical events denoted by black arrows.

Discussion

Microadenomas account for the majority of corticotroph tumors, but 7% – 23% of patients are diagnosed with a macroadenoma345. It is even rarer for a corticotroph macroadenoma to present with apoplexy with only a handful of case reports or series in the literature7. Due to its rarity, appropriate biochemical workup on presentation, such as including an ACTH with the blood work, may be omitted especially if the patient is going for emergent surgery. In this case, the undetectable prolactin can reflect loss of anterior pituitary function and also suggest a functioning corticotroph adenoma due to the inhibitory effect of long term serum glucocorticoids on prolactin secretion9. After undergoing TSS, the patient developed central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement. Presumably, the development of adrenal insufficiency demonstrated the remission of hypercortisolism as a result of apoplexy and/or TSS. The ACTH remains detectable likely representing residual tumor that was not obliterated by apoplexy nor excised by TSS given it location near the carotid artery and cavernous sinus. The presence of adrenal insufficiency in the setting of detectable ACTH is not contradictory as the physiological hypothalamic-pituitary-adrenal axis has been suppressed by the long-term pathological production of ACTH. IGF-1 and prolactin also failed to recover post-operatively. In CD where the production of IGF-1 and prolactin are attenuated by elevated cortisol, it would then be expected that IGF-1 and prolactin recover after hypercortisolism remission. However, the absence of this observation in our case is likely a sequalae of the apoplexy and extensive surgery leading to pituitary hypofunction.

We also want to highlight features of the pre-operative radiographical findings which can provide valuable insight into the subsequent histology. Previous literature has shown that, on T2-weight MRI, silent corticotroph adenomas are strongly correlated with characteristic a multimicrocystic appearance while nonfunctional gonadotroph macroadenomas are not correlated with this MRI finding10. The multimicrocystic appearance is described as small hyperintense areas with hyperintense striae in the solid part of the tumor (Figure 1C)10. This is an useful predictive tool for silent corticotroph adenomas with a sensitivity of 76%, specificity of 95% and a likelihood ratio of 15.310.

The ability to distinguish between silent corticotroph macroadenoma and other macroadenomas is important for assessing rate of remission and recurrence risk. In 2017, the WHO published updated classification for pituitary tumors. In this new classification, corticotroph adenomas are further divided into densely granulated, sparsely granulated and Crooke’s cell tumors11. DGCT are intensely Periodic Acid Schiff (PAS) stain positive and exhibit strong diffuse pattern of ACTH immunoreactivity, whereas SGCT exhibit faintly positive PAS alongside weak focal ACTH immunoreactivity4,12. Crooke’s cell tumors are characterized by Crooke’s hyaline changes in more than 50% of the tumor cells4. In the literature, SGCT account for an estimated 19-29% of corticotroph adenomas131415. The clinicopathological relevance of granulation pattern in corticotroph tumors was unclear until recently.

In multiple studies examining granulation pattern and tumor size, SGCT were statistically larger13,15,16. Hence, we suspect that many of the previously labelled silent corticotroph macroadenomas in the literature were SGCT. The traditional teaching of CD has been “small tumor, big Cushing and big tumor, small Cushing” which reflects the inverse relationship between tumor size and symptomatology17. This observation appears to hold true as Doğanşen et al. found a trend towards longer duration of CD in SGCT of 34 months compared to 26 months in DGCT based on patient history13,17. It has been postulated that the underlying mechanism of the inverse relationship between tumor size and symptomatology is impaired processing of proopiomelanocortin resulting in less effective secretion of ACTH in corticotroph macroadenomas3. Doğanşen et al. also found that the recurrence rate was doubled for SGCT, while Witek et al. showed that SGCT were less likely to achieve remission postoperatively13,16.

Similar to other cases of SGCT, the diagnosis was only arrived retrospective after pathological confirmation10. Interestingly, the characteristic Crooke’s hyaline change of surrounding non-adenomatous pituitary tissue was not observed as one would expect in a state of prolonged glucocorticoid excess in this case. Although classically described, the absence of this finding does not rule out CD. As evident in a recent retrospective study where 10 out of 144 patients with CD did not have Crooke’s hyaline change18. In patients without Crooke’s hyaline change, the authors found a lower remission rate of 44.4% compared to 73.5% in patients with Crooke’s hyaline change. Together with the detectable post-operative ACTH, sparsely granulated pattern and absence of Crooke’s hyaline change in surrounding pituitary tissue, the risk of recurrence is increased. These risk factors emphasize the importance of close monitoring to ensure early detection of recurrence.

Declaration of Interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Conclusion

We present a case of a sparsely granulated corticotroph macroadenoma presenting with apoplexy leading to remission of hypercortisolism and development of central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement.

References

Endoscopic Surgery Should Be Standard for Cushing’s Patients with Large Tumors

Cushing’s disease patients with macroadenomas — pituitary tumors larger than 10 mm — should undergo transsphenoidal pituitary surgery using the endoscopic technique, according to a new systematic review.

The study, “Endoscopic vs. microscopic transsphenoidal surgery for Cushing’s disease: a systematic review and meta-analysis,” was published in the journal Pituitary.

Cushing’s disease develops due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The first-choice treatment for Cushing’s disease is transsphenoidal pituitary surgery, which is performed through the nose to remove pituitary tumors.

There are two main methods to conduct this kind of surgery: microscopic, which is done using a magnifying tool, and endoscopic surgery, which uses a thin, lighted tube with a tiny camera. The microscopic technique was the established method for transsphenoidal surgery, until physicians started doing endoscopic pituitary surgery in 1992.

Most surgical centers choose to perform either the microscopic or endoscopic technique but do not offer both. As a result, only a few small studies have compared the outcomes of microscopic and endoscopic surgical techniques in Cushing’s disease performed at the same center. These studies showed no clear differences in remission rates or surgical morbidity.

To date, no systematic review comparing the microscopic and the endoscopic surgical techniques in Cushing’s disease has been conducted and, therefore, convincing evidence to support either technique is lacking.

To address this, researchers set out to conduct a systematic review and meta-analysis that compares the endoscopic and microscopic transsphenoidal surgery techniques for Cushing’s disease with regards to surgical outcomes and complication rates.

Researchers searched through nine electronic databases to identify potentially relevant articles. In total, 97 cohort studies with 6,695 patients were included in the study. Among the total patient population, 5,711 received microscopical surgery and 984 were endoscopically operated.

Overall remission was achieved in 80 percent of patients, with no clear differences between the techniques. The recurrence rate was around 10 percent, and short-term mortality was less than 0.5 percent.

Cerebrospinal fluid leak (due to a hole or a tear) occurred more often in patients who underwent endoscopic surgery. On the other hand, transient diabetes insipidus — short-term diabetes — occurred more often in patients who received endoscopic surgery.

When classifying patients by tumor size, however, researchers found that patients with macroadenomas — tumors larger than 10 mm — had higher rates of remission and lower recurrence rates after endoscopic surgery. Patients with microadenomas (tumors smaller than 10 mm) had comparable outcomes with either technique.

“Endoscopic surgery for patients with Cushing’s disease reaches comparable results for microadenomas, and probably better results for macroadenomas than microscopic surgery,” the investigators wrote.

Taking these results into account, the researchers suggest that endoscopic surgery may be considered the current standard of care, though microscopic surgery can be used based on the neurosurgeon’s preference.

They also emphasize that centers that solely perform the microscopic technique should consider at least referring Cushing’s disease patients with macroadenomas to a center that performs the endoscopic technique.

From https://cushingsdiseasenews.com/2018/05/24/endoscopic-surgery-more-effective-macroadenomas-cushings-study/

Intraoperative MRI improves complete resection of pituitary macroadenoma

A 63-year-old man was referred to the Massachusetts General Hospital Neuroendocrine & Pituitary Tumor Clinical Center for management of a pituitary macroadenoma. He experienced increasingly severe retro-orbital headaches in the past year. He reported no double vision, fatigue, orthostatic dizziness, change in beard growth or reduction in libido. An outside head CT scan showed an enlarged pituitary gland.

Imaging and laboratory tests

A pituitary MRI with magnified pituitary slices and gadolinium contrast was ordered. A well-circumscribed “snowman-shaped” sellar mass was identified, measuring 2.6 cm x 2 cm x 1.8 cm (anteroposterior x transverse x craniocaudal) with suprasellar extension (Figure 1). The lesion was heterogeneous on T1-weighted scans after enhancement with IV gadolinium contrast. An area of hypointensity in the superior margin was consistent with a small area of cystic or hemorrhagic degeneration.

Although the mass did not extend laterally into the cavernous sinus, the sellar mass extended upward into the suprasellar cistern through a hole in the dural, the diaphragma sellae, to compress the optic chiasm. The restriction of adenoma growth by the diaphragma sellae results in the snowman shape of the macroadenoma. The optic chiasm and infundibulum (pituitary stalk) could not be identified on coronal or sagittal images (Figure 1). Visual field on confrontation suggested lateral field deficits (bilateral lateral hemianopsia) that were confirmed on formal Goldmann kinetic perimetry visual fields.

Figure 1. Preoperative MRI scan. A large “snowman-shaped” pituitary adenoma (green arrow) has heterogeneous enhancement after gadolinium contrast administration. A small hypodense area in the adenoma likely represented hemorrhage/cystic degeneration (yellow arrow). The tumor does not surround the carotid siphon, an S-shaped portion of the internal carotid artery (red arrows) within the cavernous sinus located laterally from the sella turcica where the pituitary gland resides. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

Source: Stephanie L. Lee, MD, PhD, ECNU. Reprinted with permission.

Initial hormonal evaluation was normal and included morning adrenocorticotropic hormone 18 pg/mL, cortisol 13.64 µg/dL, thyroid-stimulating hormone 2.14 uIU/mL, free thyroxine 1.2 ng/dL and prolactin 12.6 ng/mL. The patient’s morning testosterone level was normal at 324 ng/dL, with follicle-stimulating hormone 2.4 mIU/mL and luteinizing hormone 1.6 mIU/mL. His insulin-like growth factor I level was normal at 124 ng/mL.

Tumor resection

The patient was treated preoperatively with stress-dose hydrocortisone 50 mg. He then underwent transsphenoidal pituitary tumor resection. After the surgeon believed there was an adequate excision of the tumor, the extent of tumor resection was confirmed by an intraoperative MRI (Figure 2 on page 8).

Figure 2. Intraoperative MRI scan. The large macroadenoma is not seen after transsphenoidal surgery. The optic chiasm (yellow arrow) can be seen after removal of the tumor. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

The operation was concluded after the imaging confirmed the complete resection of the pituitary adenoma. The patient’s postoperative course was uneventful. Imaging 4 weeks after the resection confirmed complete resection of the suprasellar mass with residual enhancement of the resection bed and sphenoid sinuses (Figure 3 on page 8). The postoperative MRI revealed a normal optical chiasm and a downward tending of the infundibulum to the residual pituitary gland located inferiorly along the sella turcica (pituitary fossa) of the sphenoid bone. Pathology confirmed a pituitary adenoma. His anterior and posterior pituitary function were normal 6 weeks postoperatively, and his visual field deficit improved.

Intraoperative MRI

Imaging like that used in this case occurs in a specially designed operating room that allows MRI scans during surgery without moving the patient from the surgical table. The MRI is kept in a shielded enclosure during the procedure and then moved along a track into the operating room for imaging. Clinical indications for the use of intraoperative MRI in neurosurgery include resection of pituitary macroadenomas. In the past, these tumors underwent transsphenoidal resection, and the postoperative MRI was performed after 1 or more days after the procedure to check for complete removal. If residual tumor was found, the patients underwent watchful waiting, external radiation or repeat surgery.

The strategic advantage of an intraoperative MRI is that the imaging is performed during the operative procedure, and if there is any residual tumor, surgery can be resumed after the MRI is moved back into the shielded enclosure.

Figure 3. Four-week postoperative MRI scan. The large macroadenoma is not seen after the transsphenoidal survey. The optic chiasm and infundibulum (pituitary stalk) can be seen after resection of the tumor. The pituitary stalk is deviated to the left of the sella where the residual normal thyroid is locate along the sella turcica. The floor of the sella enhances with gadolinium infusion after surgery due to postoperative inflammation. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

It has been reported that the use of intraoperative MRI does not increase complication rates compared with conventional transsphenoidal surgery. Reports on the improvement of gross tumor resection using intraoperative MRI are variable, perhaps due to the expertise of the surgeon. Several reports suggest the use of intraoperative MRI allowed additional resection of noninvasive macroadenomas in 67% to 83% of the patients with a gross tumor resection. These results suggest that a substantial volume reduction and increased gross tumor resection of pituitary macroadenomas occurs with the use of intraoperative MRI compared with standard surgery. One study demonstrated that the gross tumor resection rates of invasive tumors was also improved with the use of intraoperative MRI compared with usual preoperative imaging and surgery (25% vs. 7%).

The use of intraoperative MRI, especially with transsphenoidal reoperations for invasive and noninvasive pituitary macroadenomas, leads to significantly higher “gross tumor resection” rates. This method prevents additional operations or treatment, such as radiation, because it reduces the number of patients with residual adenoma after surgery. This technology is usually found in specialized tertiary care hospitals but should be considered for reoperation for large pituitary macroadenomas or initial operation for large invasive pituitary macroadenomas.

Disclosures: Lee and Swearingen report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/print/endocrine-today/%7B23183444-4d29-477b-844f-6eb995ac74f4%7D/intraoperative-mri-improves-complete-resection-of-pituitary-macroadenoma

Imaging Technique Measures Tumor Stiffness to Aid Surgical Planning

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Important steps in planning tumor surgery include identifying borders between tumor and healthy tissue and assessing the tumor stiffness, e.g. hard and calcified or soft and pliant. For decades, tumors near the surface of the body have been evaluated for stiffness by simple palpation—the physician pressing on the tissue. Because tumors within the skull cannot be palpated, researchers used Magnetic Resonance Elastography (MRE) to assess pituitary tumor stiffness by measuring waves transmitted through the skull into pituitary macroadenomas (PMAs). MRE reliably identified tumors that were soft enough for removal with a minimally-invasive suction technique versus harder tumors requiring more invasive surgery.

“The group developed brain MRE several years ago and is now successfully applying it to clinical diagnosis and treatment,” explained Guoying Liu, Ph.D., Director of the NIBIB Program in Magnetic Resonance Imaging. “This development of a new imaging technique followed by its practical application in surgical planning for better patient outcomes is an outstanding example of one of the main objectives of NIBIB-funded research.”

MRE is a special magnetic resonance imaging technique that captures snapshots of shear waves that move through the tissue and create elastograms—images that show tissue stiffness. John Huston III, M.D., Professor of Radiology at the Mayo Clinic in Rochester, MN, and senior author of the study, explains how MRE works. “MRE is similar to a drop of water hitting a still pond to create the ripples that move out in all directions. We generate tiny, harmless ripples, or shear waves, that travel through the brain of the patient. Our instruments measure how the ripples change as they move through the brain and those changes give us an extremely accurate measure–and a color-coded picture–of the stiffness of the tissue.”

MRE data enables non-invasive surgical planning

Ninety percent of PMAs are soft—nearly the consistency of toothpaste. Therefore, without MRE, surgeons would routinely plan for a procedure called transphenoidal resection that employs very thin instruments that are threaded through the nasal cavity to the pituitary gland at the base of the skull, where suction is used to remove the tumor. However, in about 10% of the cases, the surgeon will encounter a hard tumor. At that point an attempt is made to break-up the tumor—essentially chipping away at it with sharp instruments. If that is not successful, the surgeon must perform a fully-invasive craniotomy that involves removing a piece of the skull bone in order to fully expose the tumor.

The more extensive procedure means added risk and discomfort for patients, and up to a week-long recovery in the hospital compared to the transphenoidal approach that allows patients to leave the hospital in a day or two. Using MRE, hard PMAs can be identified and the more extensive craniotomy can be planned before starting the surgery, which makes the more invasive procedure less taxing for both the surgeon and patient. Similarly, MRE showing a soft PMA gives surgeons confidence that the nasal entry and removal by suction will be successful-eliminating the likelihood that the surgeon may need to perform a second fully-invasive craniotomy.

In the study of PMA reported in the January 2016 issue of the journal Pituitary, the group performed pre-surgical MRE evaluation of the PMAs of 10 patients.The MRE measurements were compared to tumor classifications made by inspection of the tumor during surgery. The surgeons categorized six tumors as soft and four tumors as medium. No tumors were deemed to be hard. The comparison of the MRE results and reports of stiffness by the surgeons when the tumor was removed and inspected were in close agreement, which was confirmed by statistical analysis.

Future plans

Although brain MRE is not yet widely available, Huston explained that the surgeons at the Mayo Clinic are now routinely using MRE to plan the best procedure for the removal of PMAs as well as several other types of brain tumor. And, even though this study of the 10 PMA patients is a very small set, Huston believes that as Mayo surgeons continue to use MRE in planning, the technique will likely begin to be adopted by other surgical centers.

Huston explained that an important aspect of some of the other brain tumor types, which the surgeons are finding extremely useful, is the ability of MRE to identify tumor adhesion to the brain. Adhesion refers to whether the brain tumor and healthy brain tissue are connected by an extensive network of blood vessels and connective tissue. This is in comparison with a tumor that is in the brain but is isolated from healthy tissue.

When MRE is used to analyze this aspect of the tumor, it clearly identifies those that are non-adhered, showing a border around the tumor through which there are no vascular connections. Conversely, MRE of adhered tumors show no border between the tumor and healthy brain, indicating extensive vascular and soft tissue connections between brain and tumor. Mutual blood vessels make removal of adherent tumors much more difficult, with a much higher chance of damage to healthy tissue and potential loss of function for the patient.

Huston and his colleagues are continuing to apply MRE, often called “palpating by imaging” to diagnosis of other brain disorders. In addition to characterizing focal brain disorders such as tumors, the group is testing the potential for MRE to provide diagnostic information about diffuse brain disease, and are currently using MRE brain stiffness patterns to identify different types of neural disorders including dementia.

This research was funded by the National Institutes of Health through the National Institute of Biomedical Imaging and Bioengineering grant EB001981.

Magnetic resonance elastography detects tumoral consistency in pituitary macroadenomas. Hughes JD, Fattahi N, Van Gompel J, Arani A, Ehman R, Huston J 3rd. Pituitary. 2016 Jun;19(3):286-92

From http://www.rdmag.com/news/2017/01/imaging-technique-measures-tumor-stiffness-aid-surgical-planning

Macroadenoma biochemical behavior in pediatric patients with Cushing’s disease differs from adult cases

Cushing’s disease in children is associated with similar biochemical measures whether the disease is due to macroadenomas or microadenomas, according to a presentation at the AACE 24th Annual Scientific & Clinical Congress.

This contrasts with the disease behavior in adults, in whom macrodenomas demonstrate less glucocorticoid suppression and adrenocorticotropic hormone (ACTH) response to laboratory tests than do microadenomas, according to researchers.

“Children with pituitary macroadenomas are more likely to have the classical response to Cushing’s disease functional testing as microadenomas,”Ricardo Correa, MD, a clinical and research endocrinology fellow at National Institutes of Health, told Endocrine Today.

Correa and colleagues conducted a retrospective review of patients with Cushing’s disease who were younger than 18 years when they were admitted to the NIH between 1997 and 2014. All Cushing’s diagnoses were confirmed by pathology.

Pituitary macroadenoma was identified in 13 patients (69% female) and microadenoma in 74 (58% female). The groups had similar mean age (14 years) and BMI (31.8 kg/m2 and 30.2 kg/m2 for macroadenoma and microadenoma, respectively). The macroadenoma group had a median (25% to 75%) 24-hour urine free cortisol of  263.60 mcg/24 hr (range 170.7-528) compared with 371.6 mcg/ 24 hr (range 244.2-625.3) in the microadenoma group (P = 0.47). Median 24-hr urinary 17-hydroxysteroid excretion in the macroadenoma group was 12.6 mg/24 hr (range 8.9-42.5) and 31.6 mg/24 hr (range 4.3-39.9) in the microadenoma group.

Mean morning serum cortisol was 38.9 ± 40.4 mcg/dL compared with  20.2 ± 15.8 mcg/dL in the macroademona and microadenoma groups, respectively (P = 0.16). Mean morning basal plasma ACTH was 106.3 ± 112.3 pg/mL compared with 49.9±44.3 pg/mL for the macroadenoma and microadenoma groups, respectively (P = 0.11), while ACTH responses to the ovine corticotropin-releasing hormone test revealed no statistically significant differences. Using the high dose dexamethasone suppression test, 58% (7/12) suppressed more than 69% in the macroadenoma group compared to 69% (44/64) in the microadenoma group (P = .51).

“Studies in adult patients have demonstrated that macroadenomas have less glucocorticoid suppressibility after the high-dose dexamethasone suppression test and attenuated ACTH response to CRH compared to pituitary microadenomas,” according to Correa. “However, the present study shows that this is not true in children; although patients with macroadenomas had a tendency for higher baseline serum ACTH and cortisol levels, their responses to dynamic testing were similar to those with microadenomas.”

Reference:

Correa R, et al. Abstract #803. Presented at: AACE 24th Annual Scientific & Clinical Congress; May 13-17, 2015; Nashville, Tenn.

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7Bb4fbf36f-ac88-4eff-9278-90f0a8d1aec2%7D/macroadenoma-biochemical-behavior-in-pediatric-patients-with-cushings-disease-differs-from-adult-cases?sc_trk=internalsearch

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