Elsevier

World Neurosurgery

Volume 97, January 2017, Pages 140-155
World Neurosurgery

Original Article
Aggressive Pituitary Adenomas: The Dark Side of the Moon

https://doi.org/10.1016/j.wneu.2016.09.092Get rights and content

Background

Although pituitary adenomas are considered benign lesions, a small group may show clinically aggressive behavior, sometimes independently from the classic markers of aggressiveness, including the Ki67 labeling index or p53 expression.

Methods

We selected 7 patients harboring a pituitary tumor with clinical features of aggressiveness. Patients underwent a full preoperative and postoperative endocrinologic and neuroradiologic workup. Two were nonfunctioning, 2 prolactin-secreting, 2 adrenocorticotrophic hormone–secreting, and 1 a growth hormone–secreting adenoma.

Results

The 7 patients underwent a total of 17 surgical procedures. At the first surgical procedure, gross total removal was achieved in none of the patients, whereas subtotal removal (>90% of tumor removed) was achieved in 4/7 cases and partial removal (<90% of tumor removed) in 3/7 cases. At first operation, 4/7 patients showed a Ki67 index ≤3% and 2/7 >3%; this information was not available for 1 patient.

Postoperatively, all patients underwent radiation therapy. Three patients received chemotherapy with temozolomide. Three patients underwent peptide receptor radionuclide therapy. To date, 1 patient has died of tumor progression, and 2 patients are in a poor general condition. The remaining 4 patients are in a fair/good condition, without any major complaints. The mean follow-up is 43.42 months.

Conclusions

Aggressive pituitary adenomas represent a specific and still underestimated entity, often diagnosed late. Clinical and neuroradiologic rapid progression is often the only marker of aggressiveness. Surgical debulking remains the first therapeutic option. Multidisciplinary management is mandatory to offer these patients targeted therapeutic options.

Introduction

Although pituitary adenomas are usually believed to be benign lesions, as many as 25%–55% of pituitary adenomas are considered to be invasive,1, 2 and some show a clinically more aggressive behavior.3, 4

The World Health Organization classification for endocrine tumors distinguishes the pituitary tumors, according to various ultrastructural features, as typical, atypical, and pituitary carcinomas, but such classification does not necessarily correlate with clinical behavior. Atypical adenomas are not necessarily invasive nor do they always show recurrence or a clearly aggressive behavior,5, 6 whereas aggressive adenomas, even with a malignant evolution, may often show ultrastructural features of a typical pituitary adenoma.7 Aggressiveness of pituitary adenomas might be related to immunophenotype changing, silent adrenocorticotrophic hormone (ACTH)-secreting adenomas, silent growth hormone (GH)-secreting adenomas, thyroid-stimulating hormone–secreting adenomas, adenomas with a proliferation index of >15%, and so on. There are still some lesions that do not have such immunohistochemical features and still clinically behave aggressively.

This lack of a correlation between immunohistochemistry and clinical behavior is also highlighted by heterogeneous terminology: the term aggressive is often wrongly used as synonymous for invasive, merging 2 different entities, thus limiting the feasibility and the effectiveness of an early diagnosis. Aggressive pituitary tumors require closer clinical and radiologic surveillance and more complex and multidisciplinary management.

As a consequence of the lack of a standard definition, no previous studies have been published reporting data about the management of this subgroup of pituitary adenomas. The few exceptions are small series and case reports, focusing on the role of temozolomide as a salvage therapy in patients unresponsive to conventional treatments.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19

We report our experience, describing a series of 7 patients harboring an aggressive pituitary adenoma, focusing on the fundamental role of a multidisciplinary approach for this challenging and not yet fully understood disease.

Section snippets

Methods

By reviewing the pertinent literature,6, 20, 21, 22 we identified the most common features typically shown by pituitary tumors with aggressive behavior.

We considered:

  • Invasion and/or infiltration of the surrounding structures

  • Rapid growth to large size

  • Tendency to recur rapidly

  • Resistance to conventional treatments.6

Rapid growth and tendency to recur rapidly may be considered as 2 sides of the same coin and for this reason, we decided to retrospectively analyze patients harboring at least 3 of 4 of

Results

From 2007 to 2015, 7 patients (4 women and 3 men; mean age, 44.14 years; range, 35–63 years) affected by an aggressive pituitary adenoma, according to the criteria outlined earlier, were treated at the Multidisciplinary Pituitary Center of the University of Messina (Table 1 and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8 showing illustrative cases from our series).

Two had nonfunctioning pituitary adenomas, 2 had prolactin (PRL)-secreting, 2 had ACTH-secreting,

Discussion

No large series of aggressive pituitary adenomas have been reported in the literature. As a consequence, no reliable markers for aggressiveness (biohumoral, histopathologic, immunohistochemical, molecular or neuroradiologic) are available for early detection of this subgroup of pituitary adenomas. This situation is probably also related to a lack of standardization of terminology.

We analyzed a small subgroup of patients harboring aggressive pituitary adenomas. The disappointing results in the

Conclusions

The so-called aggressive pituitary adenomas are a specific entity, lying between benign adenomas and malignant pituitary carcinomas. They show a rather distinct clinical behavior with massive invasion of surrounding tissues, rapid growth, tendency to recur rapidly, resistance to conventional treatments, and, in some patients, a fatal outcome.

Considering the lack of specific tools available for their early identification, they are often diagnosed late, thus reducing the chances of a good

References (76)

  • S. Chiloiro et al.

    Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis

    Neuroendocrinology

    (2015)
  • G. Raverot et al.

    Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience

    J Clin Endocrinol Metab

    (2010)
  • M. Losa et al.

    Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases

    Eur J Endocrinol

    (2010)
  • Z.M. Bush et al.

    Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression

    J Clin Endocrinol Metab

    (2010)
  • T. Hirohata et al.

    DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors

    J Clin Endocrinol Metab

    (2013)
  • M.S. Thearle et al.

    Temozolomide (Temodar(R)) and capecitabine (Xeloda(R)) treatment of an aggressive corticotroph pituitary tumor

    Pituitary

    (2011)
  • L.M. Neff et al.

    Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists

    Pituitary

    (2007)
  • K. Kovacs et al.

    MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy

    Acta Neuropathol

    (2008)
  • V.J. Moyes et al.

    Treatment of Nelson's syndrome with temozolomide

    Eur J Endocrinol

    (2009)
  • C. Hagen et al.

    Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy

    Eur J Endocrinol

    (2009)
  • A.I. McCormack et al.

    Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours

    Clin Endocrinol (Oxf)

    (2009)
  • T.H. Dillard et al.

    Temozolomide for corticotroph pituitary adenomas refractory to standard therapy

    Pituitary

    (2011)
  • A. Heaney

    Management of aggressive pituitary adenomas and pituitary carcinomas

    J Neurooncol

    (2014)
  • A. Di Ieva et al.

    Aggressive pituitary adenomas–diagnosis and emerging treatments

    Nat Rev Endocrinol

    (2014)
  • E. Chatzellis et al.

    Aggressive pituitary tumors

    Neuroendocrinology

    (2015)
  • D.O. Gesellschaft

    Empfehlungen zur Beurteilung der Minderung der Erwerbsfähigkeit durch Schäden des Sehvermögens

    Der Augenarzt

    (1981)
  • D.O. Gesellschaft

    Empfehlungen zur Beurteilung der Minderung der Erwebsfähigkeit durch Schäden des Sehvermögens

    Klin Mbl Augenheilk

    (1982)
  • E. Knosp et al.

    Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings

    Neurosurgery

    (1993)
  • W. Saeger et al.

    Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry

    Eur J Endocrinol

    (2007)
  • D.H. George et al.

    Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma

    Am J Surg Pathol

    (2003)
  • K. Kovacs et al.

    Prognostic indicators in an aggressive pituitary Crooke's cell adenoma

    Can J Neurol Sci

    (2005)
  • O. Mete et al.

    Biomarkers of aggressive pituitary adenomas

    J Mol Endocrinol

    (2012)
  • O. Mete et al.

    Clinicopathological correlations in pituitary adenomas

    Brain Pathol

    (2012)
  • J. Hardy

    Transphenoidal microsurgery of the normal and pathological pituitary

    Clin Neurosurg

    (1969)
  • F. Salehi et al.

    Biomarkers of pituitary neoplasms: a review (Part II)

    Neurosurgery

    (2010)
  • A.P. Heaney

    Clinical review: pituitary carcinoma: difficult diagnosis and treatment

    J Clin Endocrinol Metab

    (2011)
  • H.E. Turner et al.

    Are markers of proliferation valuable in the histological assessment of pituitary tumours?

    Pituitary

    (1999)
  • G. Kontogeorgos

    Predictive markers of pituitary adenoma behavior

    Neuroendocrinology

    (2006)
  • Cited by (32)

    • Medical treatment of aggressive pituitary tumors

      2021, Pituitary Tumors: A Comprehensive and Interdisciplinary Approach
    • Aggressive Pituitary Adenomas and Carcinomas

      2020, Endocrinology and Metabolism Clinics of North America
      Citation Excerpt :

      However, we try to decrease TMZ to a half-dose after 24 cycles in order to limit the potential cumulative toxicity. The main other treatment options have been recently reviewed by our team30 and involve a limited number of patients: 20 patients treated with peptide receptor radionuclide therapy (PRRT),19,20,28,31–37 12 treated with bevacizumab (a vascular endothelial growth factor receptor–targeted therapy),2,20,38–42 10 treated with tyrosine kinase inhibitors,20,43,44 6 treated with everolimus (a mammalian target of rapamycin inhibitor),20,45–47 and 2 patients treated with immune checkpoint inhibitors.48,49 Not enough data are available to draw any definitive conclusion, but, based on the radiological response, the therapies currently showing the most promise are bevacizumab, PRRT, and immune checkpoint inhibitors.30

    • Cyberknife stereotactic treatment of pituitary adenomas: A single center experience using different irradiation schemes and modalities

      2019, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
      Citation Excerpt :

      This could be explained by the use of the single-session scheme (typical of GK) in 60% of patients that probably is more effective in controlling the endocrine disease than the hypofractionated scheme (usually used by CK). CK treatment is usually considered a second-line therapy in cases of PAs showing a volumetric progression and/or hormonal hypersecretion resistant to other therapies, or in patients not eligible to other therapies including surgery (i.e. high anaesthesiological risk, refusing surgical treatment) [6–14]. In our series, the CK treatment was reserved as first line therapy in four patients: three refused surgery and one was affected by a giant aggressive adenoma and serious comorbidities that contra-indicated surgical resection.

    • Clinical Parameters to Distinguish Silent Corticotroph Adenomas from Other Nonfunctioning Pituitary Adenomas

      2018, World Neurosurgery
      Citation Excerpt :

      Our study results may help facilitate early detection of SCAs, enhancing the chance of a good outcome. To achieve the best results, these kinds of aggressive tumors require closer clinical and radiologic surveillance and more complex and multidisciplinary management.39 Follow-up testing is recommended 6 months after the initial testing and annually thereafter in patients with a pituitary macroincidentaloma.9

    • Multimodal therapy in aggressive pituitary tumors

      2020, Endocrinologia, Diabetes y Nutricion
      Citation Excerpt :

      In 2015, an acromegalic patient because an invasive macroadenoma treated with of 90Y-DOTATATE achieved partial biochemical remission and a reduction in the tumor size.177 Priola et al.3 selected 7 patients with aggressive pituitary tumor. Three of them with intense pituitary mass uptake in 111In-DTPA-octreotide scintigraphy received PRRT.

    View all citing articles on Scopus

    Conflict of interest statement: This study was supported in part by the Grant PON02_00643_3604826 from MIUR (Italian Ministry of University and Research).

    View full text