adenoma

Pituitary adenoma recurrence

Pituitary adenoma recurrence

Tumor recurrence or residual regrowth are poor prognosis for pituitary adenoma.

A comprehensive review of the literature quantified the pituitary adenoma recurrence rates for commonly observed pituitary adenomas after transsphenoidal surgical resection with curative intent. Findings suggest that surveillance within 1 year may be of low yield. Further, clinical trials and cohort studies investigating the cost-effectiveness of surveillance schedules and their impact on the quality of life of patients under surveillance will provide further insight to optimize follow-up 1).

The old 2004 World Health Organization classification introduced atypical adenoma, which was equivocally defined as an invasion with increased mitotic activity that had a Ki67 labeling index (LI) greater than 3%, and extensive p53 immunoreactivity. However, aPAs that exhibit all of these features are rare and the predictive value for recurrent pituitary adenomas (PAs) remains uncertain.

Remission is lowest in patients with nonfunctioning adenomas, and recurrence is highest in patients with a prolactinoma. The remission rate has not improved over 3 decades of publication, but there is a modest decrease in recurrences with time. The highest incidence of tumor recurrence is between 1 and 5 years after surgery. Surgery-related hypopituitarism was highest in Cushing’s disease. The most important predictor for recurrence is the postoperative basal (non-stimulated) hormone level in functioning adenomas, while in nonfunctioning adenomas no single convincing factor could be identified 2).

With a high rate of recurrence, Nonfunctioning pituitary adenomas (NFPA) should be closely followed-up over a long-term period. Improvement of surgical techniques with advanced surgical equipment and adjuvant radiosurgery would lead to reduce the recurrence rate and improve patients’ outcome 3).

Pituitary adenoma recurrence risk

Postoperative residue, age, immunohistological subtypes, invasion, tumor size, hormone levels, and postoperative radiotherapy can predict the risk of recurrence in patients with PAs. Additionally, biomarkers such as Ki-67, p53, cadherin, pituitary tumor transforming gene, matrix metalloproteinase-9, epidermal growth factor receptor, fascin actin-bundling protein 1, cyclooxygenase-2, and some miRNAs and lncRNAs may be utilized as valuable tools for predicting PA recurrence. As no single marker can independently predict PA recurrence, we introduce an array of comprehensive models and grading methods, including multiple prognostic factors, to predict the prognosis of PAs, which have shown good effectiveness and would be beneficial for predicting PA recurrence 4).

There is no validated and well-accepted prognostic classification of PAs to predict the clinical outcome and guide clinical practice. Tumor recurrence or residual regrowth identified by MRI scans and endocrine studies and associated clinical and pathological characteristics were analyzed for patients who underwent surgery in the years 2008-2016 at West China Hospital. Thereby, a new clinicopathological classification was proposed and applied.

After a median follow-up of 44.0 months, tumor recurrence and residual progression were identified in 48 (25.0%) and 29 (37.2%) cases, respectively. Proliferative potential (HR=2.188, p=0.002), invasiveness (HR=1.698, p=0.029), larger tumor size (HR=1.029, p=0.004), high-risk PA subtype (HR=2.151, p=0.004) and postoperative residual (HR=1.941, p=0.007) were risk factors for recurrence/progression in the early stage after surgery. With respect to clinicopathological classification, compared with Grade 1a tumors, Grade 1b, 2a and 2b adenomas had poorer prognoses with an increased probability of tumor recurrence/progression of 5.133-, 4.467- and 20.1-fold, respectively.

The proposed clinicopathological classification of PAs showed significant value in predicting prognosis and succeeded in identifying cases with more clinically aggressive lesions with recurrence or residual regrowth. This prognostic classification may be helpful when identifying aggressive PAs and deciding the appropriate therapeutic strategy for patients with PAs 5).

1)

Caulley L, Whelan J, Khoury M, Mavedatnia D, Sahlollbey N, Amrani L, Eid A, Doyle MA, Malcolm J, Alkherayf F, Ramsay T, Moher D, Johnson-Obaseki S, Schramm D, Hunink MGM, Kilty SJ. Post-operative surveillance for somatotroph, lactotroph and non-functional pituitary adenomas after curative resection: a systematic review. Pituitary. 2022 Nov 23. doi: 10.1007/s11102-022-01289-x. Epub ahead of print. PMID: 36422846.
2)

Roelfsema F, Biermasz NR, Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary. 2012 Mar;15(1):71-83. doi: 10.1007/s11102-011-0347-7. Review. PubMed PMID: 21918830; PubMed Central PMCID: PMC3296023.
3)

Lee MH, Lee JH, Seol HJ, Lee JI, Kim JH, Kong DS, Nam DH. Clinical Concerns about Recurrence of Non-Functioning Pituitary Adenoma. Brain Tumor Res Treat. 2016 Apr;4(1):1-7. doi: 10.14791/btrt.2016.4.1.1. Epub 2016 Apr 29. PubMed PMID: 27195254; PubMed Central PMCID: PMC4868810.
4)

Lu L, Wan X, Xu Y, Chen J, Shu K, Lei T. Prognostic Factors for Recurrence in Pituitary Adenomas: Recent Progress and Future Directions. Diagnostics (Basel). 2022 Apr 13;12(4):977. doi: 10.3390/diagnostics12040977. PMID: 35454025; PMCID: PMC9024548.
5)

Lv L, Yin S, Zhou P, Hu Y, Chen C, Ma W, Jiang Y, Wang Z, Jiang S. Clinical and pathological characteristics predicted the postoperative recurrence and progression of pituitary adenoma: a retrospective study with 10 years follow-up. World Neurosurg. 2018 Jul 4. pii: S1878-8750(18)31426-8. doi: 10.1016/j.wneu.2018.06.210. [Epub ahead of print] PubMed PMID: 29981466.

Pituitary adenoma

Pituitary adenoma

Pituitary adenoma (PA) is a common pituitary tumor that arises from the adenohypophysis, in the pituitary gland.

Epidemiology

Pituitary adenoma epidemiology.

Classification

see Pituitary adenoma classification.

Risk factors

Pituitary tumors have very few known risk factors, and these are related to genetics. There are no known environmental or lifestyle-related risk factors for pituitary tumors. Though science has suggested that people who are overweight or obese might be at increased risk.

Youn et al. discovered that a 3’untranslated region (3’UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA.

Although further studies are needed to verify the impact of this variant on pituitary adenoma susceptibility, the results may help to understand CDKN2B polymorphism and the risk of pituitary adenoma 1).

Genetic syndromes

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 4

McCune-Albright syndrome

Carney complex

Pathogenesis

Pituitary adenoma pathogenesis

Natural History

see Pituitary adenoma Natural History.

Clinical features

see Pituitary adenoma clinical features.

Diagnosis

Pituitary Adenoma Diagnosis.

Treatment

see Pituitary adenoma treatment.

Outcome

Pituitary Adenoma Outcome.

Recurrence

see Pituitary adenoma recurrence.

Case series

see Pituitary adenoma case series.

1)

Youn BJ, Cheong HS, Namgoong S, Kim LH, Baek IK, Kim JH, Yoon SJ, Kim EH, Kim SH, Chang JH, Kim SH, Shin HD. Asian-specific 3’UTR variant in CDKN2B associated with risk of pituitary adenoma. Mol Biol Rep. 2022 Sep 12. doi: 10.1007/s11033-022-07796-1. Epub ahead of print. PMID: 36097105.

Clinically non-functioning pituitary adenoma

Clinically non-functioning pituitary adenoma

Clinically non-functioning pituitary adenoma (CNFPA) is currently the preferred term for designing all the pituitary adenomas which are not hormonally active (in other words, not associated with clinical syndromes such as amenorrhea–galactorrhea in the context of Lactotroph adenomas, acromegaly, Cushing’s disease or hyperthyroidism secondary to TSH secreting pituitary adenoma).

Epidemiology

see Clinically non-functioning pituitary adenoma epidemiology.

Natural history

Clinically non-functioning pituitary adenoma natural history.

Classification

Clinically non-functioning pituitary adenoma classification.

Pathogenesis

Clinically non-functioning pituitary adenoma pathogenesis.

Clinical features

Clinically non-functioning pituitary adenoma clinical features.

Scores

Knosp Grade

Diagnosis

Clinically non-functioning pituitary adenoma diagnosis.

Differential diagnosis

Clinically non-functioning pituitary adenoma differential diagnosis

Treatment

see Clinically non-functioning pituitary adenoma treatment.

Outcome

see Clinically Non-functioning Pituitary Adenoma Outcome.

Case series

see Clinically non-functioning pituitary adenoma case series.

Case reports

Clinically non-functioning pituitary adenoma case reports

Invasive pituitary adenoma

Invasive pituitary adenoma

Invasive pituitary adenomas are benign pituitary tumors that infiltrate the dura mater, cranial bone, or sphenoid sinus. Gross invasion at the time of operation is observed in up to 35 % of pituitary adenomas 1) 2) 3).

Clinically nonfunctioning pituitary adenoma (NFPA) is a very common type of intracranial tumor, which can be locally invasive and can have a high recurrence rate.

Atypical or aggressive pituitary adenomas are tumors that rapidly increase in size and may invade into the suprasellar or parasellar regions. They are characterized by a Ki-67 nuclear labeling index greater than 10 %.

Molecular markers

Invasive pituitary adenoma molecular markers.

Clinical features

They can be presented as Non-pulsatile exophthalmos.

Infrequently they produce cerebrospinal fluid rhinorrhea.

Differential diagnosis

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable from pituitary adenoma until identification of metastases.

Treatment

Invasive pituitary adenoma treatment.

Outcome

Aggressive pituitary adenomas (APAs) are pituitary tumors that are refractory to standard treatments and carry a poor prognosis.

Case reports

A 57-year-old man presented with visual deterioration and bitemporal hemianopsia. MRI of the brain demonstrated a sellar mass suspected to be pituitary macroadenoma with a displacement of the stalk and optic nerve impingement. The patient underwent stereotactic endoscopic transsphenoidal resection of the mass. Postoperative MRI demonstrated gross total resection. Pathology revealed a sparsely granulated corticotroph adenoma with malignant transformation. Immunohistochemistry showed a loss of expression of MLH1 and PMS2 in the tumor cells. Proton therapy was recommended given an elevated Ki67 index and p53 positivity. Before radiotherapy, there was no radiographic evidence of residual tumor. Temozolomide therapy was initiated after surveillance MRI showed recurrence at 16 months postoperatively. However, MRI demonstrated marked progression after 3 cycles. Next-generation sequencing using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C. Immunotherapy with ipilimumab/nivolumab was initiated, and MRI demonstrated no residual tumor burden 34 months postoperatively.

APA is a tumor with frequent recurrence and a short median expected length of survival. Shah et al. demonstrated the utility of immunotherapy in a single case report of APA, with complete resolution of recurrent APA and improved survival compared with a life expectancy 4).

References

1)

Oruçkaptan HH, Senmevsim O, Ozcan OE, Ozgen T. Pituitary adenomas: results of 684 surgically treated patients and review of the literature. Surg Neurol. 2000;53:211–219.
2)

Scheithauer BW, Kovacs KT, Laws ER, Jr, Randall RV. Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 1986;65:733–744.
3)

Selman WR, Laws ER, Scheithauer BW, et al. The occurrence of dural invasion in pituitary adenomas. J Neurosurg. 1986;64:402–407.
4)

Shah S, Manzoor S, Rothman Y, Hagen M, Pater L, Golnik K, Mahammedi A, Lin AL, Bhabhra R, Forbes JA, Sengupta S. Complete Response of a Patient With a Mismatch Repair Deficient Aggressive Pituitary Adenoma to Immune Checkpoint Inhibitor Therapy: A Case Report. Neurosurgery. 2022 May 13. doi: 10.1227/neu.0000000000002024. Epub ahead of print. PMID: 35544035.

Somatotroph adenoma

Somatotroph adenoma

Somatotroph adenomas (GH producing adenomas, somatotropinomas) are typically recognized when they secrete GH excessively and cause the clinical syndrome of acromegaly. This recognition not only identifies a sellar mass as a somatotroph adenoma but also expands the therapeutic options. Occasional reports in the literature also describe ‘silent somatotroph adenomas,’ referring to adenomas that can be identified as somatotroph adenomas by positive immunohistochemical staining for GH, but are not associated with clinical evidence of GH excess. Some of these adenomas are totally silent, in that they are not associated with either clinical manifestations of GH excess or elevated serum concentrations of GH or IGF1.

Epidemiology

75 % of Somatotroph adenomas are > 10 mm at time of diagnosis.

Pathogenesis

Somatotroph adenoma pathogenesis.

Classification

Somatotroph adenoma classification.

Clinical Features

Somatotroph adenoma clinical features.

Diagnosis

Somatotroph adenoma diagnosis.

Treatment

see Somatotroph adenoma treatment.

Outcome

see Somatotroph adenoma outcome

Case series

Somatotroph adenoma case series.

Case reports

Somatotroph adenoma case reports.

Transsphenoidal approach for pituitary adenoma

Transsphenoidal approach for pituitary adenoma

Cerebrospinal fluid fistula after transsphenoidal surgery for pituitary adenomas may be prevented by skull base reconstruction with fat autograft. However, graft changes may interfere with the interpretation of postoperative images. The aim of Cossu et al. was to describe the radiological evolution of the fat autograft.

A retrospective analysis was performed, including patients undergoing transsphenoidal surgery for pituitary adenomas with a fat autograft for skull base reconstruction. Clinical and radiological data were collected, with an assessment of fat autograft and the extent of resection. Statistical analysis was performed using Kruskal-Wallis and Wilcoxon signed-rank test while Spearman’s Rho was used to analyze the relationship between variables.

Seventy-two patients were included. Macroadenomas was diagnosed in 62 cases (86.1%) and in 21 cases an invasion of the cavernous sinus was described (29%). Gross total resection was achieved in 84.7% of cases. The volume of the fat graft significantly decreased between 3 months and 1 year after surgery (p = 0.01) and between 1 year and the last follow-up (mean 4.63 years, p < 0.01). Fat signal ratio significantly diminished between 3 months and 1 year in unenhanced and enhanced T1-weighted sequences (p = 0.04 and p = 0.02 respectively). Volume reduction was related to the decrease in the signal ratio in unenhanced T1 sequences (p = 0.008).

Fat resorbs with time: almost 50% of the fat volume is lost during the first year after surgery and 60% is resorbed at 4.6 years. T1-signal, before and after gadolinium injection, also decreases during the first year, probably because of the progressive fibrosis of the graft. This information will contribute to the interpretation of postoperative images 1).

The aim of a study of Butenschoen et al. was to analyze the postoperative improvement of visual function after adenoma resection and to identify prognostic factors for the postoperative clinical recovery. They performed a retrospective analysis of all consecutive patients treated via a transsphenoidal approach for pituitary adenomas from April 2006 to December 2019 in a high-volume neurosurgical department. The primary outcome was postoperative visual acuity and visual field impairment; the clinical findings were followed up to 3 months after surgery and correlated with clinical and radiographic findings. In total, 440 surgeries were performed in our department for tumors of the sella region in a time period of 13 years via a transsphenoidal approach, and 191 patients included in the analysis. The mean age was 55 years, and 98% were macroadenomas. Mean preoperative visual acuity in patients with preoperative impairment (n = 133) improved significantly from 0.64/0.65 to 0.72/0.75 and 0.76/0.8 (right eye R/left eye L) postoperatively and at 3 months follow-up (p < 0.001). Visual acuity significantly depended on Knosp classification but not Hardy grading. The strongest predictor for visual function recovery was age. Transsphenoidal pituitary tumor resection remains a safe and effective treatment in patients with preoperative visual impairment. It significantly improves visual acuity and field defects after surgery, and recovery continues at the 3 months follow-up examination 2).

Dai et al. quantitatively synthesized the comparative efficacy and safety of the most common surgical approaches including endoscopic transsphenoidal approach, sublabial transsphenoidal microsurgery (STMS) and endonasal transsphenoidal microsurgery (ETMS) for all kinds of pituitary tumors. This systematic review and network meta-analysis were performed on randomized controlled trials (RCTs) and comparison studies from databases of Pubmed, EMBASE, and the Cochrane Library. They selected the rate of gross complete resection as the primary outcome of efficacy. And the incidence of all complications, cerebrospinal fluid (CSF) leak, diabetes insipidus, nasal septal perforation, death, and bleeding were designed as our primary outcomes of safety. Twenty-seven studies with 2618 patients were included in this network meta-analysis. On efficacy, there was no statistical difference among the three methods including ETES, STMS, and ETMS. As for safety, results indicated that the incidence of total complications of STMS (OR = 4.74; 95% CI 1.03, 40.14) is significantly superior to ETES. And the incidence of diabetes insipidus of ETMS (OR = 2.21; 95% CI 1.31, 3.81) was significantly superior to that of ETES. Besides, there was no statistical difference in the other complications including CSF leak, nasal septal perforation, death, and bleeding. They clarified the overpraise of the efficacy of endoscopy especially the endonasal transsphenoidal approach and verified that all the approaches owned similar efficacy. Moreover, they recommended the endoscopy to be the first choice for pituitary tumors, because it demonstrated the best safety 3).

The transsphenoidal approach is the gold standard for pituitary adenoma resection. However, despite advances in microsurgical and endoscopic techniques, some pituitary adenomas can be challenging to cure.

Traditionally performed with a microscope and a sublabial incision, the implementation of the endoscopic visualization and endonasal access has rendered the transsphenoidal approach less invasive and provided improved visualization into and around the sella.

see Endoscopic transsphenoidal approach

The standard endonasal approach has been expanded to provide access to other, parasellar lesions. With the addition of the endoscope, this expansion carries significant potential for the resection of skull base lesions.

see Extended endoscopic transsphenoidal approach

Although there is limited and low quality evidence available, the use of intraoperative ultrasound appears to be a safe and effective technological adjunct to transsphenoidal surgery for pituitary adenoma. Advances in ultrasound technology may allow for more widespread use of such devices 4).

Suprasellar extension is regarded a drawback for complete removal of these tumors through this approach.

Is very important to evaluate the correlation between the preoperative radiologic craniocaudal extension on MRI of pituitary adenomas and the extent of tumor removal. A retrospective study. Tertiary care hospital. 560 patients underwent transsphenoidal removal of pituitary adenomas. The degree of removal of pituitary tumor in the follow-up imaging of the patients was correlated with the preoperative extension in mid-Coronal T1 W Gd. Tumors with suprasellar extension can be classified into: Type I tumors with extension confined to the sellar boundaries, resulted in complete removal in all cases (100%), type II tumors with suprasellar extension reaching the floor of the 3rd ventricle, resulted in complete removal in 70.2% of the cases, type III tumors with suprasellar extension above the 3rd ventricle, had only 13.5% of complete removal. Integration of radiologic findings into a scheme for the preoperative determination of possibility of total removal of the tumor through transsphenoidal approach, can give better correlation to the surgical outcome of pituitary tumors 5).

Costs

Geographic variations in healthcare costs have been reported for many surgical specialties.

In a study, Asemota et al. sought to describe national and regional costs associated with transsphenoidal pituitary surgery (TPS).

Data from the Truven-MarketScan 2010-2014 was analyzed. We examined overall total, hospital/facility, physician, and out-of-pocket payments in patients undergoing TPS including technique-specific costs. Mean payments were obtained after risk-adjustment for the patient- and system-level confounders and estimated differences across regions.

The estimated overall annual burden was $43 million/year in our cohort. The average overall total payment associated with TPS was $35,602.30, hospital/facility payment was $26,980.45, physician payment was $4,685.95, and out-of-pocket payment was $2,330.78. Overall total and hospital/facility costs were highest in the West and lowest in the South (both P<0.001), while physician reimbursements were highest in the North-east and lowest in the South (P<0.001). There were no differences in out-of-pocket expenses across regions. On a national level, there were significantly higher overall total and hospital/facility payments associated with endoscopic compared to microscopic procedures (both P<0.001); there were no significant differences in physician payments nor out-of-pocket expenses between techniques. There were also significant within-region cost differences in the overall total, hospital/facility, and physician payments in both techniques as well as in out-of-pocket expenses associated with microsurgery. There were no significant regional differences in out-of-pocket expenses associated with endoscopic surgery.

These results demonstrate significant geographical cost disparities associated with TPS. Understanding the factors behind disparate costs is important for developing cost containment strategies 6).

References

1)

Cossu G, Turin-Huet V, Garvayo Navarro M, Papadakis G, Daniel RT, Dunet V, Messerer M. Radiological evolution of autograft fat used for skull base reconstruction after transsphenoidal surgery for pituitary adenomas. Pituitary. 2022 Feb 22. doi: 10.1007/s11102-022-01210-6. Epub ahead of print. PMID: 35194708.
2)

Butenschoen VM, Schwendinger N, von Werder A, Bette S, Wienke M, Meyer B, Gempt J. Visual acuity and its postoperative outcome after transsphenoidal adenoma resection. Neurosurg Rev. 2020 Oct 10. doi: 10.1007/s10143-020-01408-x. Epub ahead of print. PMID: 33040306.
3)

Dai W, Zhuang Z, Ling H, Yang Y, Hang C. Systematic review and network meta-analysis assess the comparative efficacy and safety of transsphenoidal surgery for pituitary tumor. Neurosurg Rev. 2020 Feb 8. doi: 10.1007/s10143-020-01240-3. [Epub ahead of print] PubMed PMID: 32036504.
4)

Marcus HJ, Vercauteren T, Ourselin S, Dorward NL. Intraoperative Ultrasound in Patients Undergoing Transsphoidal Surgery for Pituitary Adenoma: A Systematic Review. World Neurosurg. 2017 Jul 20. pii: S1878-8750(17)31154-3. doi: 10.1016/j.wneu.2017.07.054. [Epub ahead of print] Review. PubMed PMID: 28736351.
5)

Hamid O, El Hakim A, El Husseiny H, El Fiky L, Kamel S. Craniocaudal extension as an indication of surgical outcome in transsphenoidal surgery for pituitary adenomas. Indian J Otolaryngol Head Neck Surg. 2013 Aug;65(Suppl 2):231-5. doi: 10.1007/s12070-011-0350-3. Epub 2011 Nov 27. PubMed PMID: 24427652.
6)

Asemota AO, Ishii M, Brem H, Gallia GL. Geographic Variation in Costs of Transsphenoidal Pituitary Surgery in the United States. World Neurosurg. 2020 Mar 4. pii: S1878-8750(20)30420-4. doi: 10.1016/j.wneu.2020.02.145. [Epub ahead of print] PubMed PMID: 321454

Lactotroph adenoma treatment

Lactotroph adenoma treatment

Dopamine agonists such as bromocriptine and cabergoline have been found to be an effective treatment for hyperprolactinemia, not only inducing adenoma shrinkage but also lowering serum prolactin levels. Among known dopamine agonists, cabergoline is the drug of choice due to its enhanced tolerability compared with bromocriptine 1).

Surgical intervention may resurface as an alternative first-line treatment. When used in combination with cabergoline, surgery offers a higher disease remission rate than either drug or operation alone 2)

Lactotroph Adenoma Surgery is safe and efficient. It is particularly suitable for enclosed prolactinomas. The patient should be well informed of the pros and cons of the treatment options, which include dopamine agonist (DA) and transsphenoidal microsurgery, and the patient’s preference should be taken into account during decision-making 3).

In the absence of visual deficits, pituitary apoplexy in lactotroph adenomas is the only type of pituitary tumor for which medical therapy (Dopamine agonists) may be the primary treatment.

Issues and questions to be addressed in this approach to long-term management of prolactinomas include the frequency of radiographic monitoring, effect of pregnancy and menopause, safety of estrogen in women taking oral contraceptives, and the potential for discontinuation of dopamine agonist therapy 4).

Lactotroph adenoma Medical Therapy

see Dopamine agonist for Lactotroph adenoma.

Lactotroph Adenoma Surgery

see Lactotroph Adenoma Surgery

Controversies

Although transsphenoidal surgery (TSS) is an option for prolactinoma treatment, it is less effective than medical management, carries considerably more risk, and is more expensive. The benefit/risk ratio for DA therapy compared to TSS actually becomes increasingly more favorable as tumor size increases. Therefore DA should remain the clear treatment of choice for essentially all patients with prolactinomas, reserving TSS as a second-line option for the very small number of patients that do not tolerate or are completely resistant to DA therapy 5).

Radiosurgery

Lactotroph adenoma radiosurgery.

Serial imaging

The underlying decision to perform serial imaging in prolactinoma patients should be individualized on a case-by-case basis. Future studies should focus on alternative imaging methods and/or contrast agents 6).

References

1)

Krysiak R, Okopien B. Different Effects of Cabergoline and Bromocriptine on Metabolic and Cardiovascular Risk Factors in Patients with Elevated Prolactin Levels. Basic Clin Pharmacol Toxicol. 2014 Aug 13. doi: 10.1111/bcpt.12307. [Epub ahead of print] PubMed PMID: 25123447.
2)

Chen TY, Lee CH, Yang MY, Shen CC, Yang YP, Chien Y, Huang YF, Lai CM, Cheng WY. Treatment of Hyperprolactinemia: A Single-Institute Experience. J Chin Med Assoc. 2021 Jul 13. doi: 10.1097/JCMA.0000000000000584. Epub ahead of print. PMID: 34261980.
3)

Giese S, Nasi-Kordhishti I, Honegger J. Outcomes of Transsphenoidal Microsurgery for Prolactinomas – A Contemporary Series of 162 Cases. Exp Clin Endocrinol Diabetes. 2021 Jan 18. doi: 10.1055/a-1247-4908. Epub ahead of print. PMID: 33461233.
4)

Schlechte JA. Long-term management of prolactinomas. J Clin Endocrinol Metab. 2007 Aug;92(8):2861-5. Review. PubMed PMID: 17682084.
5)

Bloomgarden E, Molitch ME. Surgical treatment of prolactinomas: cons. Endocrine. 2014 Aug 12. [Epub ahead of print] PubMed PMID: 25112227.
6)

Varlamov EV, Hinojosa-Amaya JM, Fleseriu M. Magnetic resonance imaging in the management of prolactinomas; a review of the evidence. Pituitary. 2019 Oct 28. doi: 10.1007/s11102-019-01001-6. [Epub ahead of print] Review. PubMed PMID: 31659622.

Pituitary adenoma with gangliocytoma

Pituitary adenoma with gangliocytoma

AKA Mixed Gangliocytoma–Pituitary Adenoma

Gangliocytomas originating in the sellar region are rare; most are tumors composed of gangliocytic and pituitary adenomatous elements, forming the so-called mixed gangliocytoma-pituitary adenoma. The majority of mixed gangliocytoma adenomas are associated with endocrinopathies, mainly acromegaly and less often Cushing disease and hyperprolactinemia.

Differentiating these mixed tumors from conventional pituitary adenomas can be difficult pre-operatively, and careful histological analysis after surgical resection is key to differentiating the two entities. There is little literature addressing the possible mechanisms for the development of mixed pituitary adenoma-gangliocytomas; however, several hypotheses have been proposed. It still remains unclear if these mixed tumors differ from a clinical perspective to pituitary adenomas; however, the additional neural component of the gangliocytoma does not appear to modify the aggressiveness or risk of recurrence after surgical resection. We report a unique case of acromegaly secondary to a mixed GH-secreting pituitary adenoma, co-existing with an intrasellar gangliocytoma.

Acromegaly due to a mixed GH-secreting pituitary adenoma and intrasellar gangliocytoma is rare. These mixed tumors cannot be distinguished easily from ordinary pituitary adenomas on the basis of clinical, endocrine or neuroradiologic findings, and histological analysis is required for a definitive diagnosis. Surgical resection is usually sufficient to provide a cure, without the need for adjuvant therapy. These mixed tumors appear to have a good prognosis although the natural history is not well defined 1).

Pathogenesis

The pathogenesis of these mixed tumors remains debatable, and ongoing research is required 2).

Case series

10 cases of mixed gangliocytoma and somatotroph adenomas were evaluated for patterns of cellular differentiation and expression of lineage-specific transcription factors. The tumors were characterized by immunohistochemistry for pituitary hormones, cytokeratins, Pit-1, and the neuronal markers NeuN, neurofilaments (NFP), and MAP2. Double-labeling immunohistochemistry for Pit-1/GH, Pit-1/NFP, Pit-1/MAP2, and NeuN/GH was performed in 9/10 tumors. The data demonstrate that both adenomatous and ganglionic cells express the acidophilic lineage transcription factor Pit-1. Although mixed gangliocytomas and somatotroph adenomas show histologically distinct cellular populations, there is at least a small population of cells that coexpress the Pit-1 transcription factor and neuronal-associated cytoskeletal proteins favoring the theory of transdifferentiation of neuroendocrine cells into neuronal elements of these mixed tumors 3).

Case reports

Although pituitary macroadenomas often cause mass effects on surrounding structures, it is extremely rare for pituitary lesions to disturb cerebrospinal fluid circulation. Sellar gangliocytoma-pituitary adenomas (SGPAs) (Pituitary adenoma with gangliocytoma) are also extremely rare.

Ryder et al., reported the unique case of a man with the unusual combination of acromegaly from an SGPA, who presented with unilateral hydrocephalus. A 60-year-old man presented with rapid neurological deterioration, bitemporal hemianopsia, and acromegalic features. Neuroimaging revealed a large sellar lesion extending superiorly into the left foramen of Monro, causing acute obstructive unilateral hydrocephalus. External ventricular drain placement improved consciousness immediately. The biochemical assessment confirmed acromegaly. Following transsphenoidal debulking, histology revealed a mixed gangliocytoma/sparsely-granulated somatotrophinoma. Despite the residual disease, his vision recovered remarkably, low-dose cabergoline controlled residual excess growth hormone (GH) secretion, and the residual tumour has remained extremely stable over 2 years. Hydrocephalus is an extremely rare complication of pituitary lesions, and unilateral hydrocephalus has never been reported previously. GH secretion in SGPAs is more common than for pituitary adenomas in general, raising questions regarding the aetiology and therapeutic approach to this rare combination tumour 4).

A 67-year-old woman with a past history of type 2 diabetes mellitus presented with worsening glycemic control. She had some acromegaly symptoms and magnetic resonance imaging demonstrated a pituitary tumor. Endocrinological examination found the resting growth hormone (GH) level within the normal range, but elevated insulin-like growth factor 1 level. A 75 g oral glucose tolerance test showed inadequate suppression of nadir GH levels. Acromegaly due to GH-secreting pituitary tumor was diagnosed. The patient underwent endoscopic transsphenoidal surgery resulting in gross total removal of the tumor and recovered well postoperatively. Histological examination of the tumor showed coexistence of relatively large gangliocytoma cells and pituitary adenoma cells, suggesting mixed gangliocytoma-pituitary adenoma. In addition, colocalization of GH and GH-releasing hormone (GHRH) in pituitary adenoma cells was revealed, so the adenomatous components were more likely to produce GHRH in our mixed gangliocytoma-pituitary adenoma case. Mixed gangliocytoma-pituitary adenoma is very rare, and the present unique case demonstrated only the adenomatous components associated with GHRH production.

Sellar gangliocytoma coexisting with pituitary adenoma is recognized as a mixed gangliocytoma-pituitary adenoma and is very rare. A proposed developmental mechanism of growth hormone (GH)-secreting mixed gangliocytoma-pituitary adenoma involves GH-releasing hormone (GHRH) produced by the gangliocytic components promoting the growth of tumor including GH-secreting adenomatous components. Since the present case indicated that the adenomatous components of mixed gangliocytoma-pituitary adenoma could secrete both GH and GHRH simultaneously, progression of GH-secreting mixed gangliocytoma and pituitary adenoma may involve exposure to spontaneously produced GHRH due to the adenomatous components 5).

Two 47-year-old females who presented with masses in the sellar region following a general examination and radiological imaging. The two patients underwent sellar region tumor resection via the trans-naso-sphenoid approach. The histopathological examination confirmed the diagnosis of a hormone-free pituitary adenoma with gangliocytoma. The two patients were in good condition and experienced no specific discomfort subsequent to the follow-up after surgery. Gangliocytoma is a slowly growing and non-metastasizing tumor. A biopsy is required to differentiate a gangliocytoma from a malignant neuroblastoma, and excision is usually curative 6).

Three cases of a composite sellar tumor composed of a gangliocytoma and an adenoma are presented. Two patients who showed acromegaly and hyperprolactinemia had a gangliocytoma and a growth hormone (GH)-prolactin cell adenoma in close proximity. The gangliocytoma contained growth hormone-releasing hormone (GHRH) by immunohistochemistry. At the electron microscopical level, the gangliocytoma was characterized by numerous synaptic vesicles. The third patient, a child with Cushing’s disease, presented a corticotropin-releasing hormone (CRH)-positive gangliocytoma in close contact with an adrenocorticotropic hormone (ACTH) secreting adenoma, the latter a typical densely granulated ACTH cell adenoma. Ultrastructurally, the gangliocytoma revealed synaptic vesicles and sparse secretory granules. The results suggest that gangliocytomas may promote the development of pituitary adenomas by hypersecretion of releasing hormones. Whereas 20 cases of sellar GHRH producing gangliocytomas in acromegaly are reported in the literature, the combination of a CRH-positive gangliocytoma and an ACTH cell adenoma in Cushing’s disease is apparently the first case 7).

1) , 2)

Lee MH, McKelvie P, Krishnamurthy B, Wang YY, Caputo C. An intrasellar pituitary adenoma-gangliocytoma presenting as acromegaly. Endocrinol Diabetes Metab Case Rep. 2017 Apr 27;2017:17-0035. doi: 10.1530/EDM-17-0035. PMID: 28469929; PMCID: PMC5409941.
3)

Lopes MB, Sloan E, Polder J. Mixed Gangliocytoma-Pituitary Adenoma: Insights on the Pathogenesis of a Rare Sellar Tumor. Am J Surg Pathol. 2017 May;41(5):586-595. doi: 10.1097/PAS.0000000000000806. PMID: 28079576.
4)

Ryder S, Robusto J, Robertson T, Alexander H, Duncan EL. Unilateral hydrocephalus from a gangliocytoma-somatotrophinoma: first reported case. Endocrinol Diabetes Metab Case Rep. 2021 Jul 1;2021:EDM210037. doi: 10.1530/EDM-21-0037. Epub ahead of print. PMID: 34236040.
5)

Teramoto S, Tange Y, Ishii H, Goto H, Ogino I, Arai H. Mixed gangliocytoma-pituitary adenoma containing GH and GHRH co-secreting adenoma cells. Endocrinol Diabetes Metab Case Rep. 2019 Oct 3;2019:19-0099. doi: 10.1530/EDM-19-0099. Epub ahead of print. PMID: 31581122; PMCID: PMC6790896.
6)

Chen D, Xu J, Zhong P, Huang X, Xu M. Pituitary adenoma with gangliocytoma: Report of two cases. Oncol Lett. 2014 Aug;8(2):781-784. doi: 10.3892/ol.2014.2183. Epub 2014 May 27. PMID: 25013498; PMCID: PMC4081391.
7)

Saeger W, Puchner MJ, Lüdecke DK. Combined sellar gangliocytoma and pituitary adenoma in acromegaly or Cushing’s disease. A report of 3 cases. Virchows Arch. 1994;425(1):93-9. doi: 10.1007/BF00193956. PMID: 7921420.

Pituitary adenoma classification

Pituitary adenoma classification

They are classified based on size or cell of origin. Pituitary adenoma can be described as microadenoma, macroadenoma, and giant tumors based on size. Microadenoma is tumors less than 10 mm, while macroadenoma includes tumors larger than 10mm. Giant pituitary adenomas are more than 40 mm. There are functional pituitary adenomas in which the cell type that composes them causes increased secretion of one or multiple hormones of the anterior pituitary. Alternatively, there are Non-Functioning Pituitary Adenomas that do not secrete hormones, but they can compress the surrounding areas of the anterior pituitary leading to hormonal deficiencies 1).

The 2017 World Health Organization classification of tumors of the pituitary gland

see The 2017 World Health Organization classification of tumors of the pituitary gland.

In the fourth edition of the World Health Organization classification of endocrine tumors, are two critical changes to the classification for pituitary adenomas.

One is that the term “atypical adenoma,” which was characterized based on highly proliferative properties to predict adenomas that carry a poor prognosis, was completely eliminated due to the lack of definitive evidence. The other change is the introduction of more precise cell lineage-based classification of pituitary adenoma that is defined based on lineage-specific transcription factors and hormones produced. Accordingly, null cell adenomas have been re-defined as those that show completely negative immunostaining either for hormones or for adenohypophyseal transcription factors 2).

Somatotroph adenoma.

Lactotroph adenoma.

Tyrotroph adenoma.

Corticotroph adenoma.

Gonadotroph adenoma.

Null cell adenoma

Plurihormonal pituitary adenoma and double adenomas.

The classification is based upon the size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment, and recurrence 3).

Current classification systems for PAs are based primarily on secretory characteristics of the tumor but are also classified on the basis of phenotypical characteristics, including tumor size, degree of invasiveness (e.g., Knosp grade), and immunohistological findings 4).

The anterior WHO classification system for PAs was refined to include designations for benign adenoma, atypical adenoma, and pituitary carcinoma on the basis of p53 immunoreactivity, MIB-1 index, mitotic activity, and the absence/presence of metastases 5) 6).

These tumor types can be microadenomas or macroadenomas and can either be functional or non-functional.

By Size

Pituitary microadenoma

Pituitary macroadenoma

Giant pituitary adenoma

Volume can be calculated using MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2) transverse (TV), antero-posterior (AP) and cranio-caudal (CC).

By Function

Functioning pituitary adenoma

Nonfunctioning pituitary adenoma

Pituitary adenomas with gangliocytic component are rare tumors of the sellar region that are composed of pituitary adenoma cells and a ganglion cell component. Their histogenesis and hence nosology is not yet resolved because of the small number of cases reported and lack of large series in the literature 7).

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until the identification of metastases.

Consistency

Although most authors differentiate easily aspirated (soft) tumors from those that are not (fibrous, might require prior fragmentation), there is no universally accepted PA consistency classification. Fibrous PA tends to be hypointense on T2WI and has lower apparent diffusion coefficient (ADC) values. Fibrous tumors seemed to present higher invasion into neighboring structures, including the cavernous sinus. Several articles suggest that dopamine agonists could increase PA consistency and that prior surgery and radiotherapy also make PA more fibrous. The anatomopathological studies identify collagen as being mainly responsible for fibrous consistency of adenomas.

Conclusions: Preoperative knowledge of PA consistency affords the neurosurgeon substantial benefit, which clearly appears to be relevant to surgical planning, risks, and surgery outcomes. It could also encourage the centralization of these high complexity tumors in reference centers. Further studies may be enhanced by applying standard consistency classification of the PA and analyzing a more extensive and prospective series of fibrous PA. 8).

Knosp Grade

Knosp Grade.

Hardy’s Classification of Pituitary Adenomas

Hardy’s Classification of Pituitary Adenomas.

References

1)

Russ S, Shafiq I. Pituitary Adenoma. 2020 Feb 4. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554451/ PubMed PMID: 32119338.
2)

Inoshita N, Nishioka H. The 2017 WHO classification of pituitary adenoma: overview and comments. Brain Tumor Pathol. 2018 Apr;35(2):51-56. doi: 10.1007/s10014-018-0314-3. Epub 2018 Apr 23. Review. PubMed PMID: 29687298.
3)

Syro LV, Rotondo F, Ramirez A, Di Ieva A, Sav MA, Restrepo LM, Serna CA, Kovacs K. Progress in the Diagnosis and Classification of Pituitary Adenomas. Front Endocrinol (Lausanne). 2015 Jun 12;6:97. doi: 10.3389/fendo.2015.00097. eCollection 2015. Review. PubMed PMID: 26124750; PubMed Central PMCID: PMC4464221.
4)

Knosp E, Steiner E, Kitz K, Matula C: Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–618, 1993
5)

Barnes L, Eveson JW, Reichart P, David Sidransky: World Health Organization Classification of Tumours: Pathology and Genetics of Head and Neck Tumours Lyon, IARC Press, 2005
6)

Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr: Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg 114:336–344, 2011
7)

Balci S, Saglam A, Oruckaptan H, Erbas T, Soylemezoglu F. Pituitary adenoma with gangliocytic component: report of 5 cases with focus on immunoprofile of gangliocytic component. Pituitary. 2014 Jan 16. [Epub ahead of print] PubMed PMID: 24430434.
8)

Acitores Cancela A, Rodríguez Berrocal V, Pian H, Martínez San Millán JS, Díez JJ, Iglesias P. Clinical relevance of tumor consistency in pituitary adenoma. Hormones (Athens). 2021 Jun 19. doi: 10.1007/s42000-021-00302-5. Epub ahead of print. PMID: 34148222.

Lactotroph Adenoma Surgery

Lactotroph Adenoma Surgery

Indications

Lactotroph Adenoma Surgery is safe and efficient. It is particularly suitable for enclosed prolactinomas. The patient should be well informed of the pros and cons of the treatment options, which include dopamine agonist (DA) and transsphenoidal microsurgery, and the patient’s preference should be taken into account during decision-making 1).

In the majority of prolactinoma patients, disease remission can be achieved through surgery, with low risks of long-term surgical complications, and disease remission is less often achieved with dopamine agonists 2).

Prolactin level < 500 ng/ml in prolactinomas that are not extensively invasive: PRL may be normalized with surgery.

PRL > 500 ng/ml: the chances of normalizing PRL surgically are very low 3).

If no acute progression, an initial attempt of medical therapy should be made as the chances of normalizing PRL surgically with preop levels > 500 ng/ml are very low 4) (these tumors may shrink dramatically with bromocriptine).

If tumor not controlled medically (≈ 18 % will not respond to bromocriptine: surgery followed by restitution of medical therapy may normalize PRL).

Barrow et al. reviewed the results of transsphenoidal microsurgical management in 69 patients with prolactin-secreting pituitary adenomas who had preoperative serum prolactin levels over 200 ng/ml. The patients were divided into three groups based on their preoperative serum prolactin levels: over 200 to 500 ng/ml (Group A); over 500 to 1000 ng/ml (Group B); and over 1000 ng/ml (Group C). The percentage of successful treatment (“control rate”) was 68%, 30%, and 14%, respectively, in these three groups of patients. Based on these results, the authors offer guidelines for the management of patients with prolactin-secreting pituitary adenomas associated with exceptionally high serum prolactin levels. The surgical control rate of 68% in Group A seems to justify surgery for these patients, while primary medical care with bromocriptine is recommended for most patients with serum prolactin levels over 500 ng/ml 5).

Dopamine agonist therapy is the first line of treatment for prolactinomas because of its effectiveness in normalizing serum prolactin levels and shrinking tumor size. Though withdrawal of dopamine agonist treatment is safe and may be implemented following certain recommendations, recurrence of disease after cessation of the drug occurs in a substantial proportion of patients. Concerns regarding the safety of dopamine agonists have been raised, but its safety profile remains high, allowing its use during pregnancy. Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy 6).

Many guidelines and reports that caution against surgical treatment are based on data over a decade or more old using different techniques such as microsurgical transsphenoidal surgery or from the nascent era of endoscopic transphenoidal surgery 7).

Endoscopic techniques have continued to evolve and provide for excellent visualization, low CSF leak rates, and high rates of gross total resection. In a study of DA-resistant prolactinomas, Vroonen et al. showed that surgical debulking led to a significant de- crease in prolactin levels at a significantly lower DA dose 8).

Kreutzer et al. report a remission rate of 91 % in patients who had elective surgery of microprolactinomas, and Babey et al. also had a high long-term remission rate, without morbidity or mortality for patients with microprolactinomas 9) 10).

Cost considerations are also a concern, especially in countries such as the USA, which is undergoing rapid changes in its healthcare system. A study by Jethwa and Patel et al. found surgical resection of microprolactinomas to be more cost effective long term than medical therapy 11).

Tumor size and invasion of extrasellar and/or cavernous sinuses have typically been seen as limitations of surgery, and some patients with refractory very large or giant tumors may necessitate multistage surgical procedures with a combi- nation of endonasal and transcranial approaches.

see Lactotroph adenoma radiosurgery.

Expanded endoscopic endonasal techniques have been developed that allow for safe treatment of larger adenomas that have extra-/parasellar extension as long as the extension is in the cranio-caudal direction and not lateral to the carotids. However, the issue of partial resection and the risk of apoplexy in the residual irritated tumor is of some concern. As in many other areas of neuro-oncology, a combination approach may be optimal. Surgical resection may allow for definitive removal of the tumor and relief of the mass effect and provide tissue for precisely targeted therapies to prevent recurrence. Sophisticated immunohistochemistry and genetic testing are rapidly being applied to many other tumors and may in the future allow for superior targeted adjuvant therapies in prolactinomas and help reduce recurrences. Finally, surgery might be an answer to the long-term cost of medical therapy specifically in younger patients. However, this issue should be carefully assessed on an individual basis to not jeopardize the standard of care in prolactinoma management by unnecessary surgical treatment. Medical treatment remains the first and the treatment of choice in the general population with recently diagnosed prolactinoma in the absence of rapidly progressive neurological symptoms 12).

Costs

Few studies address the cost of treating prolactinomas.

The Department of Neurological Surgery, University of California at San Francisco, performed a cost-utility analysis of surgical versus medical treatment for prolactinomas. Materials and Methods We determined total hospital costs for surgically and medically treated prolactinoma patients. Decision-tree analysis was performed to determine which treatment produced the highest quality-adjusted life years (QALYs). Outcome data were derived from published studies. Results Average total costs for surgical patients were $19,224 ( ± 18,920). Average cost for the first year of bromocriptine or cabergoline treatment was $3,935 and $6,042, with $2,622 and $4,729 for each additional treatment year. For a patient diagnosed with prolactinoma at 40 years of age, surgery has the lowest lifetime cost ($40,473), followed by bromocriptine ($41,601) and cabergoline ($70,696). Surgery also appears to generate high health state utility and thus more QALYs. In sensitivity analyses, surgery appears to be a cost-effective treatment option for prolactinomas across a range of ages, medical/surgical costs, and medical/surgical response rates, except when surgical cure rates are ≤ 30%. Conclusion Our single institution analysis suggests that surgery may be a more cost-effective treatment for prolactinomas than medical management for a range of patient ages, costs, and response rates. Direct empirical comparison of QALYs for different treatment strategies is needed to confirm these findings 13).

References

1)

Giese S, Nasi-Kordhishti I, Honegger J. Outcomes of Transsphenoidal Microsurgery for Prolactinomas – A Contemporary Series of 162 Cases. Exp Clin Endocrinol Diabetes. 2021 Jan 18. doi: 10.1055/a-1247-4908. Epub ahead of print. PMID: 33461233.
2)

Zamanipoor Najafabadi AH, Zandbergen IM, de Vries F, et al. Surgery as a Viable Alternative First-Line Treatment for Prolactinoma Patients. A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2020;105(3):e32‐e41. doi:10.1210/clinem/dgz144
3) , 4) , 5)

Barrow DL, Mizuno J, Tindall GT. Management of prolactinomas associated with very high serum prolactin levels. J Neurosurg. 1988 Apr;68(4):554-8. PubMed PMID: 3351583.
6)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
7)

Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R, Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J, Scanlon M, Sobrinho LG, Wass JA, Giustina A (2006) Guidelines of the pituitary society for the diagnosis and management of prolactinomas. Clin Endocrinol 65:265–273
8)

Vroonen L, Jaffrain-Rea ML, Petrossians P, Tamagno G, Chanson P, Vilar L, Borson-Chazot F, Naves LA, Brue T, Gatta B, Delemer B, Ciccarelli E, Beck-Peccoz P, Caron P, Daly AF, Beckers A (2012) Prolactinomas resistant to standard doses of cabergoline: a multicen- ter study of 92 patients. Eur J Endocrinol 167:651–662
9)

Babey M, Sahli R, Vajtai I, Andres RH, Seiler RW (2011) Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists. Pituitary 14:222–230
10)

Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R, Buchfelder M (2008) Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol 158:11–18
11)

Jethwa PR, Patel TD, Hajart AF, Eloy JA, Couldwell WT, Liu JK (2015) Cost-effectiveness analysis of microscopic and endoscopic transsphenoidal surgery versus medical therapy in the management of microprolactinoma in the United States. World Neurosurg 5:2015
12)

Chakraborty S, Dehdashti AR. Does the medical treatment for prolactinoma remain the standard of care? Acta Neurochir (Wien). 2016 May;158(5):943-4. doi: 10.1007/s00701-016-2763-y. Epub 2016 Mar 11. PubMed PMID: 26965287.
13)

Zygourakis CC, Imber BS, Chen R, Han SJ, Blevins L, Molinaro A, Kahn JG, Aghi MK. Cost-Effectiveness Analysis of Surgical versus Medical Treatment of Prolactinomas. J Neurol Surg B Skull Base. 2017 Apr;78(2):125-131. doi: 10.1055/s-0036-1592193. Epub 2016 Sep 27. PubMed PMID: 28321375; PubMed Central PMCID: PMC5357228.