PNA Medical Corner: Rathke’s Cleft Cysts And IGF-1 and BMI  in Acromegaly

This month, the PNA Medical Corner features two studies co-authored by Dr. Paul Gardner, a neurosurgeon at the University of Pittsburgh School of Medicine and a member of the PNA.

The first study looks at neurosurgery for Rathke’s cleft cysts

https://pubmed.ncbi.nlm.nih.gov/38848597/

Endoscopic endonasal resection of Rathke cleft cysts: a single-institution analysis of 148 consecutive patients

Hanna N Algattas ¹, Zachary C Gersey ², David Fernandes Cabral ², Ali A Alattar ², Hussein Abdallah ², Nallammai Muthiah ², Anamil Khiyami ^3 4, Neha Mehrotra ³, Tiba Abdulwahid ³, Eric W Wang ⁵, Carl H Snyderman ⁵, Georgios A Zenonos ², Pouneh K Fazeli ³, Paul A Gardner ²

Affiliations expand

• PMID: 38848597 DOI: 10.3171/2024.3.JNS232740

Abstract

Objective: The traditional treatment of sellar Rathke cleft cysts (RCCs) generally involves transsellar drainage; however, suprasellar RCCs present unique challenges to appropriate management and technical complexity. Reports on overall outcomes for the endoscopic endonasal approach (EEA) for this pathology are limited. The EEA for RCCs allows three surgical techniques: marsupialization, fenestration, and fenestration with cyst wall resection.

Methods: The authors performed a retrospective review of consecutive patients with RCCs that had been treated via an EEA at a single institution between January 2004 and May 2021. Marsupialization entailed the removal of cyst contents while maintaining a drainage pathway into the sphenoid sinus. Fenestration involved the removal of cyst contents, followed by separation from the sphenoid sinus, often with a free mucosal graft or vascularized nasoseptal flap. Cyst wall resection, either partial or complete, was added to select cases.

Results: A total of 148 patients underwent an EEA for RCC. Marsupialization or fenestration was performed in 88 cases (59.5%) and cyst wall resection in 60 (40.5%). Cysts were classified as having a purely sellar origin (43.2%), sellar origin with suprasellar extension (37.8%), and purely suprasellar origin (18.9%). Radiological recurrence was demonstrated in 22 cases (14.9%) at an average 39.7 months’ follow-up (median 45 months, range 0.5-99 months), including 13 symptomatic cases (8.8%). Cases with cyst wall resection had no significantly different rate of recurrence (11.7% vs 15.9%, p = 0.48) or postoperative permanent anterior pituitary dysfunction (21.6% vs 12.5%, p = 0.29) compared to those of fenestrated and marsupialized cases. There was no significant difference in postoperative permanent posterior pituitary dysfunction based on technique, although such dysfunction tended to worsen with cyst wall resection (13.6% vs 4.0%, p = 0.09). Based on cyst location, purely suprasellar cysts were more likely to have a radiological recurrence (28.6%) than sellar cysts with suprasellar extension (12.5%) and purely sellar cysts (9.4%; p = 0.008). Most notably, of the 28 purely suprasellar cysts, selective cyst wall resection significantly improved the long-term (10-year) recurrence risk compared to fenestration alone (17.4% vs 80.0%, p = 0.0005) without any significant added risk of endocrinopathy.

Conclusions: Endoscopic endonasal marsupialization or fenestration of sellar RCCs may be the ideal treatment strategy, whereas purely suprasellar cysts benefit from partial cyst wall resection to prevent recurrence. Selective cyst wall resection reduced long-term recurrence rates without significantly increasing rates of hypopituitarism.

Keywords: Rathke cleft cyst; cyst resection; endoscopic endonasal approach; fenestration; marsupialization; peripheral nerve; suprasellar.

The second study looks at IGF-1 and finds that it is positively associated with BMI in patients with acromegaly.

https://pubmed.ncbi.nlm.nih.gov/36930352/

Anamil Khiyami ^1 2, Neha Mehrotra ¹, Sharini Venugopal ¹, Hussain Mahmud ¹, Georgios A Zenonos ³, Paul A Gardner ³, Pouneh K Fazeli ⁴

Affiliations expand

• PMID: 36930352 DOI: 10.1007/s11102-023-01307-6

Abstract

Purpose: Acromegaly is a disorder characterized by IGF-1 excess due to autonomous GH secretion. In individuals without acromegaly, IGF-1 is not only influenced by GH secretion but is also sensitive to other factors including nutritional status, as evidenced by the inverted U-shaped association between BMI and IGF-1; in low-weight individuals (BMI < 18.5 kg/m²) and those who are obese, IGF-1 levels may be frankly low. It is not known if this same relationship between BMI and IGF-1 is also observed in acromegaly.

Methods: Retrospective study including patients who underwent resection of a pituitary adenoma (n = 197) for either acromegaly (n = 32) or a nonfunctioning adenoma (NFPA, n = 165) at a large academic medical center between 1/1/2015 and 5/31/2021.

Results: Median BMI in acromegaly was 30.8 kg/m² (range 20.9-42.6 kg/m²). Percent upper limit of normal (%ULN) IGF-1 was 228.2% [159.0, 271.4] in acromegaly versus 32.2% [18.5, 50] in NFPA (p < 0.0001). There was a significant positive association between BMI and %ULN IGF-1 (R = 0.35, p < 0.05) in acromegaly. In contrast, there was no association between BMI and %ULN IGF-1 in the NFPA group as a whole (p = 0.22), but a significant inverse association between BMI and %ULN IGF-1 in NFPA patients with a BMI ≥ 35 kg/m² (rho = – 0.39, p = 0.02).

Conclusion: In contrast to individuals without acromegaly, BMI is significantly and positively associated with IGF-1 in acromegaly across the weight spectrum. Future studies are needed to determine if obese patients with acromegaly experience more significant symptoms related to their disease, or if patients with a low BMI may require different diagnostic criteria.

Keywords: Acromegaly; BMI; IGF-1; Obesity.

Mastering the Art of Complex Pituitary Tumor Surgery

Treatment for complex pituitary tumors often involves surgical removal. Surgery can be challenging, due to the pituitary gland’s location at the base of the skull. For optimal results, surgeons need deep knowledge of skull base anatomy.

“The anatomy is very complex, in terms of the carotid artery, other blood vessels and cranial nerve structures. But with profound understanding of that anatomy, what was very complex becomes less challenging,” says Mayo Clinic neurosurgeon Dr. Joao Paulo Cavalcante de Almeida.

Mayo Clinic’s Skull Base Lab provides education for surgeons and trainees from around the globe. A collaboration between Neurosurgery and ENT/Head and Neck Surgery, the lab is fully equipped for coursework and hands-on activities. The facility also serves as a hub for curriculum development, research and innovation in skull base surgery.

“People who come to our lab learn techniques that allow them to deliver high-quality care — which is the essential mission of our institution,” Dr. Almeida says. “This lab helps us not only to provide the best possible care for our own patients but also to spread education and innovation to other places.”

One example is training surgeons to treat pituitary tumors that invade a structure known as the medial wall of the cavernous sinus, or MWCS. These challenging tumors are associated with higher rates of recurrence. But surgical removal of the MWCS risks damaging blood vessels and nerves.

“Going into the cavernous sinus has always been a limiting factor for successful surgery of complex pituitary adenomas,” Dr. Almeida says.

The Skull Base Lab trains surgeons in selective, or partial, removal of the MWCS. The procedure can minimize complications while improving rates of tumor remission and hormone control. However, selective MWCS resection requires a profound understanding of anatomy.

“It is not a technique to be performed routinely. It should be used only by highly trained, experienced surgeons at a center of excellence with a team approach,” Dr. Almeida says. At Mayo Clinic, the team includes specialists in neurosurgery, ENT/head and neck surgery, endocrinology and radiation oncology.

Patient selection is key. The procedure is used mostly to treat functioning pituitary tumors that have clear indications of MWCS infiltration. “As we have grown more experienced, we have explored the use of selective MWCS resection in certain nonfunctioning pituitary tumors and for patients with recurrent pituitary tumors that are likely to have MWCS infiltration,” Dr. Almeida says.

Education is a core commitment at Mayo Clinic. “Successful surgery relies on the caliber of people and their training, and their ability to work as a team,” Dr. Almeida says. “Patients can benefit when we are at the top of our game.”

Mayo Clinic is one of the leading pituitary centers in the U.S.  For more information, please visit careinfo.mayoclinic.org/pituitary-tumor

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PNA Medical Corner: Cabergoline Research

Dr. Marvin Bergsneider

This month the PNA Medical Corner spotlights a study co-authored by Dr. Marvin Bergsneider of UCLA, a member of the PNA. The study looks a the way
Cabergoline works to target tumors. They describe for the first time the role of CD8+ T cells following CBG-treatment.
Cabergoline Targets Multiple Pathways to Inhibit PRL Secretion and Increases Stromal Fibrosis.
Dongyun Zhang 1, Willy Hugo 1, Marvin Bergsneider 2, Marilene B Wang 3, Won Kim 2, Karam Han 4, Harry V Vinters 4, Anthony P Heaney 1 2

https://pubmed.ncbi.nlm.nih.gov/38781434/                                                      

Abstract

Objective: Unravel potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumor and neighboring stromal and immune cells.

Design and methods: Five surgically resected prolactinomas from 3 cabergoline (CBG)-treated and 2 treatment naive patients were analyzed by single cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape.

Results: Six major cell populations that included tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%) were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components, such as perforin and the granzymes GZMB, GNLY and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in CBG-treated samples.

Conclusions: Our scRNAseq studies revealed key differences in the transcriptomic features of CBG-treated and untreated PRLomas in both tumor and microenvironment
cellular constituents, and for the first time describe previously unknown activation of CD8+ T cells following CBG-treatment which may play a role in the tumoricidal actions of CBG.

Keywords: Cabergoline; Pituitary tumor; Prolactinomas; Tumor Microenvironment; scRNAseq.
© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.

Giant pituitary adenomas need expert treatment

Giant pituitary adenomas pose special treatment challenges. Fortunately, advances in medical technology and understanding of the disease have greatly improved the management of these rare pituitary tumors. Experience and expertise are key to achieving the best possible results.

“The treatment options for giant pituitary adenomas have expanded,” says Mayo Clinic neurosurgeon Dr. Richard W. Byrne. “Several factors should be considered when planning treatment. A major multidisciplinary center can outline the best approach for each individual.”

Giant pituitary adenomas are tumors that measure more than 4 centimeters in diameter. Their size means they are often close to important nerves and blood vessels, which complicates surgical removal. Giant pituitary adenomas are also likelier than smaller tumors to cause symptoms such as vision and hormonal problems.

Surgery is the main treatment option. The goal is to improve hormonal and other symptoms while also preserving the pituitary’s function.

The minimally invasive procedure known as endoscopic transnasal transsphenoidal surgery is increasingly applied to giant pituitary adenomas. Mayo Clinic was among the first institutions to extensively research this approach.

“Endoscopic transnasal transphenoidal surgery is associated with lower postoperative complications and a higher likelihood of preserving normal pituitary and visual function. But the surgical team’s level of experience is critical,” Dr. Byrne says. “More-experienced surgeons have a better understanding of the practicalities of tumor removal because they are farther along on the learning curve.”

Tumors extending into certain brain regions generally require open surgery, or craniotomy. “There are several techniques for these open procedures, each of which has advantages and disadvantages,” Dr. Byrne says. Sometimes, open surgery is performed in combination with an endoscopic approach.

Some giant pituitary adenomas can be treated with medication. “A thorough presurgical evaluation can identify patients who might be able to avoid surgery,” Dr. Byrne says. “But it’s important to note that giant pituitary adenomas treated only with medication might need prolonged, annual imaging to detect recurrences.”

Due to their location, some giant pituitary adenomas are difficult to completely remove with surgery. Radiation therapy can be used to treat the remaining tumor. There are several options, including stereotactic radiosurgery, external beam radiation, intensity-modulated radiation therapy and proton beam therapy.

Identifying the best treatment for each individual requires a multidisciplinary team. “Collaboration among neurosurgeons, endocrinologists, and radiation oncologists is crucial for optimal patient care,” Dr. Byrne says.

Choosing the best approach for managing pituitary tumors

Some pituitary tumors don’t need treatment. They aren’t cancer, so if they don’t cause symptoms, monitoring them over time with regular imaging might be a good approach. But some pituitary tumors cause significant problems and require surgical removal.

“Surgery is usually needed if the tumor is pressing on the optic nerves and limiting eyesight, if it’s causing headache or facial pain, or if it’s affecting hormone production,” explains Mayo Clinic neurosurgeon Dr. Chandan Krishna.

The best surgical approach depends on factors such as the tumor’s size, location and growth over time. It’s important to ask your health care provider which surgery is right for you, and to talk about the possible complications, risks and side effects. Surgical options include endoscopic transnasal transsphenoidal surgery, and craniotomy.

“With a transnasal endoscopic approach, we place a surgical instrument through the nostril to access the tumor. We then remove the tumor through the nose and sinuses,” Dr. Krishna says. “The surgery doesn’t need an incision and doesn’t affect other parts of the brain.” Mayo Clinic was among the first institutions to extensively research the endoscopic through-the-nose approach. Now standard practice, the procedure lowers discomfort and usually requires only an overnight stay in the hospital. At Mayo Clinic, ENT/head and neck surgeons work alongside neurosurgeons during these procedures.

Large pituitary tumors might be hard to remove through the nose — especially if the tumor has spread to nearby nerves, blood vessels or other parts of the brain. In those cases, a surgeon generally performs a craniotomy. A small cut is placed in the scalp, and the tumor is removed through the upper part of the skull.

“Both approaches to pituitary tumor removal are generally safe procedures,” Dr. Krishna says. “Complications are uncommon.”

Radiation therapy might be recommended if surgery isn’t feasible. Radiation therapy also might be used if a tumor isn’t completely removed with surgery or if a tumor comes back after surgery. There are several options, including stereotactic radiosurgery, external beam radiation, intensity-modulated radiation therapy and proton beam therapy.

Getting a second opinion or care at a major pituitary center helps ensure the best treatment for each individual. “No two patients are alike. No two pituitary tumors are alike,” Dr. Krishna says. “Experience and expertise in the full range of treatment approaches goes a long way towards providing the best outcomes.”

Count on your Xeris CareConnection™ Team for unparalleled Cushing’s Support

Cushing’s can be challenging, but there is support so patients can feel like themselves again. The main goal of treating Cushing’s is to get cortisol levels back to normal. This Pituitary Awareness Month, Xeris Pharmaceuticals® is highlighting the importance of one-on-one support for patients living with Cushing’s Syndrome and support for HCPs treating Cushing’s Syndrome.

Sign up to get dedicated support:

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PNA Medical Corner: Age and progression-free survival with nonfunctioning pituitary adenomas

Dr. John Atkinson

Dr. Jamie Van Gompel

Dr. Maria Peris Celda

This month the PNA Medical Corner focuses on a study coauthored by three members of the PNA: Drs. John Atkinson, Jamie Van Gompel and Maria Peris Celda. They conclude that older patients with nonfunctioning pituitary tumors had better progression-free survival rates, even when they underwent aggressive surgery.

https://pubmed.ncbi.nlm.nih.gov/38669710/

Correlation of older age with better progression-free survival despite less aggressive resection in nonfunctioning pituitary adenomas

Yuki Shinya ^1 2, John L D Atkinson ¹, Dana Erickson ³, Irina Bancos ³, Carlos D Pinheiro Neto ⁴, Caroline J Davidge-Pitts ³, Maria Peris Celda ¹, Justine S Herndon ³, Sukwoo Hong ^1 2, Jamie J Van Gompel ¹

Abstract

Objective: Nonfunctioning pituitary adenomas (NFPAs) present at a wide range of ages; it is possible that variable

outcomes are based on patient age at presentation. This study aimed to explore long-term outcomes of patients with NFPAs following endonasal transsphenoidal surgery (ETS), considering age stratification.

Methods: This retrospective study included 228 patients with NFPAs who underwent ETS, with a median follow-up period of 63 months. The outcomes included progression-free survival (PFS) rates and neurological and endocrinological outcomes. Age-stratified Kaplan-Meier and Cox proportional hazards analyses were performed. Patients were classified into four age groups: ≤ 49, 50-59, 60-69, and ≥ 70 years.

Results: Age-stratified analysis showed a significant correlation between age and PFS in NFPAs (5-year PFS rates: 63.0% in those ≤ 49 years, 76.7% in those 50-59 years, 85.0% in those 60-69 years, and 88.1% in those ≥ 70 years; p = 0.001, log-rank test). Bivariate (HR 1.03, 95% CI 1.01-1.05; p = 0.001) and multivariable (HR 1.03, 95% CI 1.02-1.05; p = 0.001) analyses demonstrated that older age was significantly associated with longer PFS. Multivariable analysis also demonstrated that smaller maximum tumor diameter (HR 0.77, 95% CI 0.60-0.99; p = 0.036) and gross-total resection (HR 8.55, 95% CI 3.90-18.75; p = 0.001) were significantly associated with longer PFS. Multivariable logistic regression analysis demonstrated that only younger age was associated with postoperative improvement of male hypogonadism (HR 0.91, 95% CI 0.84-0.99; p = 0.019). Other postoperative neurological and endocrinological outcomes were not significantly associated with age.

Conclusions: Older patients with NFPAs treated with ETS demonstrated a longer PFS. Of endocrinological outcomes studied, only male hypogonadism improvement was associated with younger patient age.

Keywords: age-dependent outcome; endonasal transsphenoidal surgery; nonfunctioning pituitary adenomas; pituitary surgery

The FDA has approved NGENLA (somatrogon-ghla)

The FDA has approved NGENLA (somatrogon-ghla), a once-weekly, human growth hormone analog indicated for treatment of pediatric patients aged three years and older who have growth failure due to an inadequate secretion of endogenous growth hormone.

See the Press Release here>

Count on your Xeris CareConnection™ Team for unparalleled Cushing’s Support

Cushing’s can be challenging, but there is support so patients can feel like themselves again. The main goal of treating Cushing’s is to get cortisol levels back to normal. This Pituitary Awareness Month, Xeris Pharmaceuticals® is highlighting the importance of one-on-one support for patients living with Cushing’s Syndrome and support for HCPs treating Cushing’s Syndrome.

Sign up to get dedicated support:

Patients: Sign up for support | Recorlev® (levoketoconazole)

HCP’s: Connect with Xeris support | RECORLEV® (levoketoconazole)

Have more questions? Call for more support at 1-844-444-RCLV (7258)