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Table of Contents    
REVIEW ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 7  |  Page : 13-19

Current Status of Diagnosis and Management for Functioning Pituitary Tumors: Part I


1 Department of Endocrinology, Sterling Ramakrishna Speciality Hospital, Gandhidham, Gujarat, India
2 Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Center, Bangalore, Karnataka, India
3 Department of Endocrinology, Seth G.S. Medical College and KEM Hospital, Mumbai, Maharashtra, India

Date of Acceptance28-May-2020
Date of Web Publication24-Jun-2020

Correspondence Address:
Dr. Nalini S Shah
Emeritus Professor, Department of Endocrinology, Seth G.S. Medical College and KEM Hospital, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.287680

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 » Abstract 


Pituitary adenomas (PA) account for approximately 15% of all intracranial neoplasms. Pituitary adenomas can be of different subtypes based on the cell of origin or associated hormone hypersecretion (non-functioning pituitary adenoma, prolactinoma, somatotropinoma, corticotropinoma, thyrotropinoma, and gonadotropinoma). Functioning PAs are associated with relatively higher morbidity and mortality because of associated hormone hypersecretion syndromes. Diagnosis of functioning PA is established by biochemical confirmation of hormone hypersecretion and demonstration of a pituitary lesion on imaging. Trans-sphenoidal surgical resection of tumor represents the first-line treatment for most tumor types, except for prolactinomas where medical therapy with dopamine agonists is preferred. Radiotherapy (RT) and medical therapy are the other options for the management of PA. It is important to individualize treatment options based on tumor type, patient's clinical condition, expertise of surgeon, affordability and patient preferences. In the first part of this series, we review the presentation and management of adrenocorticotropic hormone secreting, gonadotropin secreting and aggressive PA. Despite several recent advances, the diagnosis and management of Cushing's disease is still a challenge. Modifications in magnetic resonance imaging techniques like volume interpolated 3D spoiled gradient echo sequence have improved the sensitivity to detect microcorticotropinomas. Pituitary RT, preferably conventional RT, is a useful second-line therapy for the management of CD. Besides the conventional drugs, few drugs such as pasireotide and osilodrostat have been approved by US FDA recently, whereas several others are in pipeline which provide hope for a better outcome in CD patients. Temozolomide is a useful drug for the management of aggressive PA.


Keywords: Cushing's disease, medical therapy, pituitary adenoma, radiotherapy, trans-sphenoidal surgery
Key Message: Trans-sphenoidal surgical resection of tumor represents the first-line treatment for most pituitary adenoma, except for prolactinomas where medical therapy with dopamine agonists is preferred. Pituitary radiotherapy (RT), preferably conventional RT, is a useful second-line therapy for the management of Cushing′s disease. Modifications in magnetic resonance imaging techniques like volume interpolated 3D spoiled gradient echo sequence improve the sensitivity to detect microcorticotropinomas.Temozolomide is a useful drug for the management of aggressive pituitary adenomas.


How to cite this article:
Thakkar K, Sarathi V, Shah NS. Current Status of Diagnosis and Management for Functioning Pituitary Tumors: Part I. Neurol India 2020;68, Suppl S1:13-9

How to cite this URL:
Thakkar K, Sarathi V, Shah NS. Current Status of Diagnosis and Management for Functioning Pituitary Tumors: Part I. Neurol India [serial online] 2020 [cited 2020 Jul 5];68, Suppl S1:13-9. Available from: http://www.neurologyindia.com/text.asp?2020/68/7/13/287680




Pituitary adenoma (PA) is the third most common (~15%) intracranial neoplasm and the most common (~85%) tumor in the sellar-suprasellar region.[1],[2] The incidence and prevalence of PA are ~four per 1,00,000 person-years and ~77 per 1,00,000 population respectively, which are rising over the last 2 decades probably due to improved imaging techniques and treatment outcomes.[3],[4] The prevalence increases with increasing age with the highest prevalence between the 4th and 6th decade of life.[5] Pituitary adenomas can be of different subtypes based on the cell of origin or associated hormone hypersecretion: non-functioning pituitary adenomas (NFPA), prolactinoma, somatotropinoma, corticotropinoma, thyrotropinoma, and gonadotropinoma. Prolactinoma and NFPA are the most common (~85%) types of PA.[4] Functioning PAs are associated with relatively higher morbidity and mortality because of associated hormone hypersecretion syndromes, besides mass effects and/or hypopituitarism.[6],[7] Timely diagnosis and effective treatment to control hormone hypersecretion and relieve mass effects along with replacement of deficient hormones are crucial to reduce these associated health risks.[8],[9] In this review, the diagnostic approach and treatment modalities for adrenocorticotropic hormone (ACTH) secreting, gonadotropin secreting and aggressive PAs are discussed with a focus on current and emerging diagnostic tests and medical therapies.


 » Treatment Strategies for Functioning Pituitary Tumors Top


The treatment of functioning pituitary tumors consists of one or more of the following 3 modalities: surgery, radiation therapy (RT) and medical therapy.

Surgery

Trans-sphenoidal surgery (TSS) and resection of adenoma is the first line of treatment for most patients with functioning PA (except prolactinomas) as it can achieve rapid control of hormone hypersecretion, immediate decompression of surrounding vital structures and better short as well as long term remission than other treatment modalities. It can be carried out by two different techniques: microscopic or endoscopic. Although endoscopic TSS is a lately developed advanced method, both these techniques appear equally effective with similar complication rates.[10],[11] Complications associated with TSS include hypopituitarism, transient or permanent diabetes insipidus (DI) and hyponatremia as well as surgical complications such as cerebrospinal fluid leak, meningitis, injury to surrounding structures like carotid vessels, optic nerve etc., Rates of success and complications improve significantly with experienced neurosurgeon and high-volume centres.[12]

Radiotherapy

Radiotherapy is considered a second- or third-line treatment option for patients with persistent or recurrent disease after TSS. The action of RT on PA is slow and takes months to years for hormonal normalization but it produces durable hormonal and tumor control in most patients. Conventional and stereotactic fractionated RT (CRT and SRT) are delivered in small fractions of approximately 180 to 200 cGy (45 to 50 Gy over 5-6 weeks), while stereotactic radiosurgery (SRS) is delivered in 1-2 high dose fractions (15 to 25 Gy). The effectiveness for both the modes (CRT and SRS) appear similar, but normalization of hormonal hypersecretion is slightly faster with SRS.[13],[14] Stereotactic radiosurgery is more convenient to patients as only 1-2 fractions are delivered, but the selection of patients for SRS should be done cautiously as there is a higher risk of optic nerve injury if the tumor is close to optic chiasm. Furthermore, administration of SRS in patients with unvisualized tumor on MRI (as in Cushing's disease) is challenging and is associated with higher likelihood of recurrence. Complications associated with RT include risk of hypopituitarism, slightly higher risk of stroke, neurocognitive impairment, and very rarely, risk of second brain tumor. However, these can be minimized by using techniques of conformation and stereotaxis to reduce exposure of normal brain structures.

Medical therapy

Medical therapy is considered to be a primary treatment for prolactinomas but an adjunctive therapy to surgery and/or RT for other functional PAs. Medical therapy is often continued for long duration and requires biochemical and radiologic monitoring for control of hormone hypersecretion and tumor growth respectively. Besides the currently available drugs, clinical trials are underway for some emerging medical therapies which may become available for use in near future [Table 1].
Table 1: Emerging medical therapies for functioning pituitary tumors

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 » Corticotropinoma (Cushing's Disease) Top


Cushing's disease (CD) is caused by ACTH hypersecretion from corticotropinoma which results in excess cortisol secretion from adrenals, and it represents ~4-6% of all PA. It is more frequent in females (ratio 3:1)[3] and has an incidence of ~1.6 per million population per year.[15] Cushing's disease is the most common (~70%) cause of endogenous Cushing's syndrome (CS).[16] Typical features of CS include facial plethora with mooning, thin skin, wide, reddish-purple striae with depressed margins, easy bruising and proximal muscle wasting. Other less discriminatory but frequent clinical features include central obesity, osteoporosis, hirsutism with menstrual irregularities, glucose intolerance, hypertension, depression, psychosis, and susceptibility of infections. Children with CD often present only with obesity and growth deceleration, whereas catabolic manifestations are usually less common in them.[17] Patients with uncontrolled hypercortisolism have a high mortality rate with a standardised mortality ratio of 2.5.[18] Leading causes of death in CS include cardiovascular disorders, infections, and suicides.

Diagnosis

Considering the overlapping clinical features of CS with common metabolic disorders and low incidence of endogenous CS, selecting patients for testing is crucial. Widespread testing for CS in common patient groups such as metabolic syndrome or diabetes mellitus is not productive[19] and is not recommended.[20]

It is of utmost importance to exclude exogenous glucocorticoid exposure as a cause of Cushingoid manifestations by careful history taking as iatrogenic use of glucocorticoids for various causes and through various routes is the most common cause of CS. Low 8 am serum cortisol level usually suggests the diagnosis of exogenous CS. Patients with normal or elevated 8 am serum cortisol should be further tested for endogenous CS by one of the tests mentioned in [Table 2].[20] The advantages and drawbacks of each test are summarized in [Table 2]. Performing ODST as the initial screening test followed by LDDST in ODST positive subjects gives nearly 100% specificity for the diagnosis of CS.[19]
Table 2: Diagnostic tests for initial evaluation of CD

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After confirming the diagnosis of endogenous hypercortisolism with 2 or more of the tests mentioned in [Table 2], the next step is to localize the source of ACTH or cortisol excess. Measurement of morning plasma ACTH level helps to broadly classify CS into ACTH-dependent (ACTH >20 pg/ml) and ACTH-independent (ACTH <10 pg/ml).[21] Indeterminate ACTH values (10-20 pg/ml) need further evaluation such as peripheral CRH stimulation test and re-evaluation later. Cushing's disease is the most common (~90%) cause of ACTH-dependent CS and should be differentiated from ectopic ACTH syndrome (EAS). Although plasma ACTH levels are usually more than 90 pg/ml in EAS, there is a significant overlap with CD, and hence the levels of ACTH cannot differentiate between the two.

As the majority (80-90%) of CD patients have microadenomas, a dynamic contrast pituitary MRI with spin-echo sequences should be performed in patients with ACTH-dependent CS.[21] Contrast-enhanced MRI has sensitivity and specificity of ~60% and ~87% respectively for localization of PA in CD patients. Further modifications in MRI techniques like volume interpolated 3D spoiled gradient echo sequence (VI-SGE) have been shown to improve performance of pituitary MRI in the detection of microcorticotropinomas (sensitivity: ~87.5%; specificity: 100%).[22] CRH-stimulated bilateral inferior petrosal sinus sampling (BIPSS) should be considered to differentiate CD from EAS in patients with negative pituitary imaging (no adenoma or PA <6 mm).[21] Although BIPSS is an invasive test requiring the expertise of an interventional radiologist in a specialized center, it is the gold standard test (sensitivity: 95%; specificity: 95-100%) to differentiate CD from EAS. Evaluation and treatment approach to a patient with CS is depicted in [Figure 1].
Figure 1: Approach to a patient with suspected Cushing syndrome. ACTH: adrenocorticotropic hormone, CD: Cushing disease, CRH: corticotropin releasing hormone, EAS: ectopic ACTH syndrome, IPSS: inferior petrosal sinus sampling, LDDST: low dose standard 2 mg dexamethasone suppression test, MRI: magnetic resonance imaging, ODST: overnight 1 mg dexamethasone suppression test, ULN: upper limit if normal

Click here to view


Treatment

The objectives of treatment for CD is to normalize cortisol levels as well as clinical features due to hypercortisolism, and also to manage and prevent the associated co-morbidities.

Surgery

The treatment of choice for CD patients is selective pituitary adenomectomy or rarely, hemi- or total hypophysectomy, through TSS. A complete tumor resection most often results in transient cortisol deficiency due to suppression of normal corticotrophs by the long-standing hypercortisolism which should be managed with glucocorticoid replacement until recovery of the hypothalamo-pituitary-adrenal (HPA) axis. Remission after TSS is generally defined as a morning serum cortisol level <5 μg/dl within the first few days after surgery. The remission rates after TSS vary from 52-96.6% based on the surgical expertise and criteria used to define remission.[23] Positive predictors of remission after TSS include visualization of an adenoma on imaging, size and extent of adenoma, and histopathologic confirmation of adenoma.[24] Cushing disease may recur in 15-66% of patients with documented remission after TSS.[9] Longer time taken for the recovery of HPA axis is a better predictor of sustained remission after initial TSS.[24] Repeat TSS is an option for patients having persistence or recurrence of disease after initial TSS if adenoma is visualized on MRI and appears accessible to resection, but remission rates after repeat TSS are lower than initial TSS.[25]

Radiotherapy

Radiotherapy is considered as a preferred second-line treatment modality in patients with persistent or recurrent CD after TSS.[9] Radiotherapy may also be useful as the first line therapy in patients with surgically inaccessible tumors such as those with cavernous sinus invasion. Conventional fractionated radiotherapy (CRT) as well as stereotactic radiotherapy (SRT) have produced comparable rates of remission.[25] However, the recurrence rates are higher after SRT.[24] Hence, we prefer CRT over SRT in patients with CD. There is some evidence that the use of commonly available medical management options to reduce hypercortisolism (cabergoline, ketoconazole) in peri-RT period reduces the efficacy of RT,[14],[26],[27] although further studies are warranted before recommending against the routine use of anticortisolemic drugs in patients undergoing RT.

Medical treatment

Medical therapy may be used in patients with persistent or recurrent hypercortisolism after TSS and sometimes while awaiting a response to RT. Current medical therapy is directed at three targets: to reduce ACTH secretion from corticotropinoma, inhibition of steroidogenesis in adrenals, and blocking glucocorticoid receptors. The usual dose, efficacy, and side effects of various available drugs are summarised in [Table 3], whereas those of emerging drugs are summarised in [Table 1]. Oral osilodrostat has recently been approved by the US Food and Drug Administration for the management of CD. Adrenal steroidogenesis inhibitors appear more effective in controlling hypercortisolism than pituitary-directed drugs,[25] and hence more commonly used. Due to the high cost, limited efficacy and escape from documented remission, we prefer definitive treatment options such as repeat TSS or RT over medical therapy as second-line therapy.
Table 3: Medical management of Cushing disease

Click here to view


Bilateral adrenalectomy

Bilateral adrenalectomy is usually the least preferred treatment option in patients with CD but is the preferred treatment modality in those with severe disease, requiring rapid control of hypercortisolism. Cushing disease patients undergoing bilateral adrenalectomy develop life-long adrenal insufficiency and are at risk (0-47%) for progression of corticotropinoma (Nelson syndrome).[28] It is important to replace glucocorticoids and mineralocorticoids and periodically monitor plasma ACTH levels and pituitary MRI after bilateral adrenalectomy. Although some studies have suggested that prior pituitary radiation reduces the risk of Nelson syndrome, this practice is currently not recommended.


 » Gonadotropinoma Top


Most non-functioning or hormonally silent tumors arise from the gonadotrophs but functioning gonadotropinomas are very rare. Females with these tumors usually have multiple ovarian cysts and may present with pelvic pain due to ovarian hyperstimulation. Males may have macroorchidism. High serum FSH with low LH may be the only marker of FSH hypersecretion. Furthermore, the picture may be complicated in post-menopausal females or males with testicular failure. Very high α-subunit levels and gonadotropin response to TRH help to differentiate functioning gonadotropinomas from primary hypogonadism. LH producing tumors are extremely rare and may lead to elevated testosterone levels in males. Most of the gonadotropinomas are macroadenomas. Patients usually present with mass effects, while biochemical abnormalities are usually found incidentally.

Treatment

Surgical resection of adenoma is the principal treatment for patients with gonadotropinomas and restores gonadal function and increased gonadal size.[29] Radiotherapy has been used as an adjuvant therapy for persistent or recurrent disease. Medical therapy is usually ineffective.[29]


 » Aggressive Pituitary Adenomas/pituitary Carcinomas Top


The term 'aggressive PA' is reserved for tumors that continue to grow significantly despite appropriate surgical, medical and radiotherapy.[30] Most of these tumors have high Ki67 index, p53 immunoreactivity, and increased mitosis. Aggressive PA may arise from any cell type, but ~ 20% secrete GH or prolactin. Some histologic variants of PA are particularly known to have an aggressive nature such as silent corticotropinoma.[31] Pituitary carcinoma is defined as the presence of metastasis either outside central nervous system, or as a separate focus within the brain and accounts for 0.2% of pituitary tumors.[32] Most pituitary carcinomas secrete either ACTH or prolactin. Near-total resection or debulking surgery is recommended as a primary treatment, especially if the tumor is compressing optic chiasm. Radiotherapy should be considered in all patients after surgery for durable tumor control.[30] Temozolomide, an alkylating agent that induces DNA break, is used with or without standard medical therapy in patients with aggressive PA, not responding to surgery and RT or in patients with pituitary carcinoma.[33] Although temozolomide is well tolerated by most patients, some may develop transient bone marrow suppression needing dose reduction or withdrawal of the drug.[34]


 » Conclusion Top


Functioning PA are associated with higher morbidity and mortality due to associated hormone hypersecretion syndromes besides local mass effects. The management requires the use of multiple treatment modalities (TSS, RT and medical therapy) either individually or in combination. Despite the several recent advances, the diagnosis and management of CD is still a challenge. Modifications in MRI techniques such as VI-SGE have improved the sensitivity to detect microcorticotropinomas. Selective pituitary adenomectomy through TSS is the first line of treatment whereas pituitary RT, preferably CRT, is a useful second-line therapy for the management of CD.[35-38] Besides the conventional drugs, few drugs such as pasireotide and osilodrostat have been approved by US FDA recently whereas several others are in pipeline which provide hope for a better outcome in CD patients. Temozolomide is a useful drug for the management of aggressive PA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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