Aggressive pituitary tumors (PitNETs)

Abstract

The majority of anterior pituitary tumors behave benignly, that is, they grow slowly and do not metastasize, and were therefore called adenomas. However, they would frequently invade adjacent structures, leading to recurrence. One of the misleading assumptions in their previous classification was the simplistic distinction made between adenoma and carcinoma. In the upcoming WHO 2022 classification, a new terminology will be introduced: pituitary neuroendocrine tumor (PitNET) which is consistent with that used for other neuroendocrine neoplasms. In general, aggressive PitNETs are invasive and proliferative tumors with frequent recurrences, resistant to conventional treatments, and yet virtually without metastases. At present, no single morphological or histological marker has been shown as yet to reliably predict their aggressive behavior. In terms of treatment, temozolomide (TMZ) had been considered promising and the sole therapeutic option for aggressive and malignant PitNETs following failure of standard therapies. However, recent reports have disclosed that TMZ does not provide long-term control of many aggressive PitNETs. A further multidisciplinary approach is necessary for both reliable prediction and successful management of aggressive PitNETs.

1.  Introduction

Pituitary tumors (pituitary adenomas; pituitary neuroendocrine tumors: PitNETs) are quite common. If prevalence rates from autopsy and radiological series are taken into consideration, it can be in the range of nearly 10–20% [1-6]. Most of them will go unnoticed during our lifetime whereas approximately 0.5% of them will come to require medical attention and the estimated incidence of clinically significant pituitary tumor is 40 per million persons per year [3-5]. Furthermore, the majority of the clinically apparent PitNETs are very slowly growing and behave benignly. Only a very few (approximately 0.2%) of them metastasize (craniospinal and/or systemic metastases) and are termed pituitary carcinoma (metastatic PitNETs in the WHO 2022 classification). Apart from these extremely rare pituitary carcinomas, pituitary tumors have been regarded and classified as a typical benign neoplasm.

On the other hand, depending on the criteria used, up to 20–55% of the surgically-treated PitNETs may show signs of local invasion of dura, bone, and/or surrounding structures [5, 7-12]. Not many but a few of these invasive tumors display a tendency towards resistance to standard treatments and are prone to early postoperative recurrence and, thus, become clinically aggressive/refractory. PitNETs are rarely malignant in terms of metastases, and yet, they may have the potential to be aggressive [7]. The old principle of readily dividing pituitary tumors into simply “benign” adenomas vs. “malignant” carcinomas now appears quite unsuitable.

2.  The Previous WHO Classifications

In the WHO 2004 classification, the pituitary tumor was classified into typical adenoma (8272/0), atypical adenoma (8272/1), and pituitary carcinoma (8272/3) [13]. The term “atypical” adenomas was introduced to identify tumors with an aggressive clinical behavior on histopathological markers, defined as adenoma with an elevated mitotic index and a Ki-67 proliferation index greater than 3%, as well as extensive nuclear immunostaining for p53 protein (Table 1). Unfortunately, this attempt failed. The incidence of this category was relatively variable and its prognostic significance could not be established despite more than 10 years of research on the potential utility of this classification [12, 14]. These proliferation markers criteria alone, without subsequent clinical and radiological considerations, were concluded to be insufficient to predict aggressive tumor behavior.

Table 1 Proposed definitions of “aggressive” pituitary tumors

	Proliferation	Invasion	Others
Atypical adenoma (WHO, 2004 [13])	-Ki-67: >3%, -elevated mitotic index -extensive nuclear P53 immunostaining	(–)	(–)
Grade 2b adenoma (Trouillas, 2013 [11])	At least two of the three criteria: -Ki-67: ≥3% (formalin fixative) -mitoses: n >2/10 HPF -P53: positive (>10 strongly positive nuclei/10 HPF)	-Histological and/or MRI signs of cavernous or sphenoid sinus invasion	(–)
Refractory adenoma (Dai, 2016 [19])	-Ki-67: >3% -Growth rate: >2% per month	(–)	-Early (<6 months postoperatively) and frequent recurrences -Resistant to conventional treatments and/or salvage treatment with temozolomide -Lack of metastases
High-risk adenoma (WHO, 2017 [15])	-High Ki-67 -Rapid growth	-Radiological invasion	(–)
Aggressive adenoma (ESE, 2018 [31])	-Unusually rapid tumour growth rate	-Radiological invasion	-Resistant to optimal standard therapies

HPF, high power field (0.30 mm², 400× magnification)

Due to its poor reproducibility and low predictive value, the WHO 2017 classification abandoned the use of the term “atypical” adenoma [15]. Meanwhile, the assessment of markers of tumor proliferation (mitotic count and Ki-67 proliferation index) continued to be recommended, although no specific cutoff value presented itself as an important histological marker to predict recurrence, particularly following incomplete tumor resection. In the 2017 classification, tumors with rapid growth, radiological invasion, and a high Ki-67 proliferation index were proposed to represent clinical aggressiveness and were termed “high-risk” pituitary adenomas (Table 1). In addition, it was pointed out that adenoma subtypes were the important determinant of clinical behavior. Some adenoma subtypes were introduced to demonstrate higher tendency of aggressive behavior. These included sparsely-granulated somatotroph adenoma, lactotroph adenoma in men, Crooke’s cell adenoma, silent corticotroph adenoma, and plurihormonal PIT-1-positive adenoma.

3.  Pituitary Neuroendocrine Tumor (PitNET)

In 2017, the International Pituitary Pathology Club proposed a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients [16]. Similar to other NETs, all of them may be considered to have malignant potential, malignancy being defined as local invasiveness and recurrence, with pituitary carcinomas just one end of the spectrum of PitNETs [1, 7, 17, 18]. The proposal of a nomenclature change from adenoma to PitNET caused major debates. Some people argued that the change would lead to confusion for clinicians and cause anxiety among the majority of patients with a very benign tumor. Moreover, changing the name itself would not solve the true underlying concern: how to predict and successfully manage the aggressive pituitary tumors [4, 19-23].

All the same the WHO 2022 classification adopted the term PitNET. The major reasons of the nomenclature change were: (1) the pituitary hormone-secreting cells are basically a member of neuroendocrine cells and their tumors are therefore neuroendocrine neoplasms; (2) the clinical behavior of some pituitary tumors are by definition beyond those of “adenomas” referred to as very benign epithelial tumors; and (3) the WHO proposal sought to provide a framework for the universal classification for all neuroendocrine neoplasms [18, 24, 25].

4.  Prognostic Grading System in PitNET

For other NETs, the WHO grading systems that showed clear positive correlation with the prognosis (survival rate) have been provided. They were classified into three grades by histological markers which consisted of Ki-67 proliferation index and mitotic count. In PitNETs, however, these proliferative markers alone were concluded to be ineffective to distinguish aggressive behavior in the past (that is, the aforementioned “atypical” adenoma) [15]. In the upcoming WHO 2022 classification, no new PitNET grading system is introduced.

Rindi et al. [25] proposed that PitNET grades 1, 2, and 3 should correspond to the common pituitary tumor, “high risk” tumor [15], and metastatic PitNET, respectively. It is obvious that most PitNETs (at least more than 80%) will be classified into grade 1 [1, 2, 4, 5, 11, 17, 26-32]. In addition, the survival rates of most patients with PitNET grade 1 and 2 are nearly 100%. On the other hand, mortalities related to endocrinopathies must be taken account in the long-term outcome, particularly in patients with Cushing’s disease, acromegaly, hypopituitarism, and so on. Thus, it is quite difficult to establish a PitNET grading system that significantly correlates with survival rate similar to those of the other NETs.

Meanwhile, it remains unclear whether pituitary neuroendocrine carcinomas (PitNEC) exist or not in pituitary tumors [24, 25, 33].

5.  Prediction Marker of Tumor Recurrence in PitNET

Despite numerous studies and advances in prognostic classification, no single morphological or histological marker has been shown as yet to reliably predict pituitary tumor behavior [5, 7, 11, 28-30, 34]. It is evident that the initial extent of surgical resection is a significant parameter that dramatically influences the risk of recurrence and resistance to subsequent therapies apart from drug-sensitive lactotroph tumors [27].

In 2013, Trouillas et al. [11] introduced a new five-tiered prognostic clinicopathological classification (Tables 1, 2). This classification relies on two factors, including pathological aspects of proliferation (Ki-67, mitoses, and P53) and morphometric markers of invasiveness (cavernous or sphenoid sinus invasion). This grading system has been evaluated in at least 4 independent cohorts comprising 1,992 patients [5, 35-38]. Grade 2b adenomas, i.e., invasive and proliferative tumors, of this classification are considered potentially malignant [31, 32, 39]. Up to now, this classification has been considered to be most relevant to predict recurrence and, thus, was endorsed by the current European Society of Endocrinology (ESE) 2018 guidelines [27, 29, 30] (Table 1).

Table 2 Prognostic clinicopathological classification by Trouillas J et al. [11]

Prognostic clinicopathological classification (Trouillas J, 2013)

Invasion defined as histological and/or radiological (MRI) signs of cavernous or sphenoid sinus invasion

Proliferation considered on the presence of at least two of the three criteria:

Ki-67: >1% (Bouin-Hollande fixative) or ≥3% (formalin fixative)

Mitoses: n >2/10 HPF

P53: positive (>10 strongly positive nuclei/10 HPF)

The five grades are the following:

Grade 1a: non-invasive tumour

Grade 1b: non-invasive and proliferative tumour

Grade 2a: invasive tumour

Grade 2b: invasive and proliferative tumour

Grade 3: metastatic tumour (cerebrospinal or systemic metastasis)

HPF, high power field (0.30 mm², 400× magnification)

However, the definition of invasiveness in this classification, i.e., “histological and/or radiological (MRI) signs of cavernous or sphenoid sinus invasion,” is ambiguous. It has been suggested that imaging findings of invasion are more sensitive in identifying invasive tumors compared to histology [11, 30, 33]. On MRI, Knosp’s classification is most widely used to evaluate cavernous sinus invasion of the tumor [40]. In surgical series of PitNETs, histologically proven cavernous sinus invasion was more frequent in tumors with an advanced Knosp grade, but histological invasion was verified in a few Knosp grade 1 tumors, whereas there was no invasion in some Knosp grade 3 tumors [10, 41]. Even careful endoscopic inspection of the medial wall of the cavernous sinus can be misleading in some cases. Furthermore, sphenoid sinus invasion is difficult to distinguish from simple bulging of the tumor and it is questionable whether it can serve as a marker of invasiveness [27].

At any rate, the French prognostic classification has proven that, unlike other NETs, the proliferation marker alone is insufficient, and that it is necessary to use it in combination with an assessment of invasiveness to reliably predict prognosis (recurrence) in PitNETs [11].

6.  “Aggressive” vs. “Invasive”

There has been much confusion concerning the terms “aggressive” and “invasive” to express PitNETs with aggressive behavior and poor prognosis. These terms have been interpreted differently by different clinicians and are often used interchangeably and synonymously in the literature. Currently, invasiveness is defined by radiological and surgical findings, and aggressiveness by clinical behavior [28].

In general, large/giant PitNETs with massive intracranial extensions are considered to be “aggressive” and challenging tumors by the most pituitary surgeons. Upon histological examination, however, many of the clinically nonfunctioning giant tumors turn out to be gonadotroph PitNETs without increased proliferation activity, which are not significantly different from the common non-giant nonfunctioning tumors [42-45]. It is important for pituitary surgeons to select the proper strategies for successful management of these radiologically “aggressive” but histologically benign tumors. The first step is the safe and high-level surgical resection of the tumor either by transsphenoidal, extended, or simultaneous transcranial and transsphenoidal approaches [42, 46-51]. Following precise histological assessments, adjuvant treatment including radiation treatment, medical treatment, further surgery, or wait-and-see strategy should be considered accordingly for the residual tumor.

Meanwhile, tumor size does not necessarily correlate with aggressive behavior, although aggressive PitNETs are usually macrotumors at diagnosis [5]. In addition, surgical success is not solely determined by tumor size.

On the other hand, the recent technical advances have achieved satisfactory, safe, and effective resection of tumors invading the cavernous sinus in some cases [9, 10, 40, 50, 52-54]. It is clear that an “aggressive” surgical resection of tumors invading the cavernous sinus increases the chance of endocrinological remission in functioning PitNETs. But still, tumor invasion, particularly to the cavernous sinus, is a major cause of incomplete surgical resection and a major prognostic factor determining recurrence. Although it can be difficult to define accurately, “invasiveness” is by definition a significant factor of aggressive PitNETs, as has been confirmed by the French prognostic classification [11].

7.  Definition of Aggressive/refractory PitNETs

Although highly necessary, a widely agreed-upon definition of aggressive PitNETs that can predict poor prognosis has yet to be established. Up to now, there have been some proposals to define aggressive/refractory PitNETs that represent tumors with malignant potential (Table 1).

Grade 2b adenomas, i.e., invasive and proliferative tumors, in the French prognostic classification (Table 2) are considered potentially malignant [31, 32, 39]. Dai et al. [19, 55] proposed the term “refractory” pituitary adenoma to define aggressive pituitary tumors exhibiting: 1) a high Ki-67 index and rapid growth; 2) early and high frequency of recurrence; 3) resistance to conventional treatments and/or salvage treatment with TMZ; 4) poor prognosis; and 5) a lack of cerebrospinal or systemic metastases. In the WHO 2017 classification, tumors with rapid growth, radiological invasion, and a high Ki-67 proliferation index were termed “high-risk” pituitary adenoma [15]. In 2018, the ESE guidelines proposed that the diagnosis of an aggressive pituitary tumor be considered in patients with a radiologically invasive tumor and unusually rapid tumor growth rate, or clinically relevant tumor growth despite optimal standard therapies (surgery, radiotherapy and conventional medical treatments) [30]. The estimated prevalence rates of these aggressive PitNETs vary between the reports, ranging from 0.5 to 18% [1, 2, 4, 5, 11, 17, 26-32].

8.  Prediction of Aggressive Behavior and Malignant Transformation (To Metastatic PitNETs)

The term metastatic PitNETs (pituitary carcinoma) is clearly limited to PitNETs with distinct metastases. However, the clinicopathological features of aggressive PitNETs are similar to and not substantially different from those of metastatic PitNETs. Raverot et al. and Trouillas et al. [31, 32, 39] have reported that aggressive PitNETs and metastaic PitNETs may be “two sides of the same coin.”

As has been mentioned, no histological or radiological marker alone is sufficient to reliably predict tumor behavior. In addition, there is no significant evidence correlating genetic abnormalities driving invasive and/or metastatic pituitary tumors [5]. PitNETs associated with germline mutations (e.g., AIP, MEN1, GPR101) were shown to be more invasive or resistant but were not associated with more aggressive behavior [30, 31]. Consequently, at present, the identification of potentially aggressive PitNETs should be made on an individual basis by considering the tumor subtype, proliferative potential, and tumor invasion assessment [5].

Any categorical switches from a clinically nonfunctioning tumor to a functioning one, especially from a silent corticotroph tumor to overt Cushing’s disease, as well as from a drug-sensitive tumor to a drug-resistant one should alert the physician to the potential for an aggressive (malignant) change [5, 56, 57].

It is important to note that the most common clinical presentation of aggressive PitNETs is early recurrence [28, 33]. The most significant factor of tumor recurrence is certainly a residual tumor following surgery. For surgical treatment of resectable (noninvasive) PitNETs, pituitary surgeons should always make utmost efforts to resect tumors both radically and safely [27, 28, 50]. For unresectable PitNETs including invasive tumor, adequate histological evaluation is essential for making a postoperative therapeutic decision. Early induction of adjuvant treatment and close follow-up are necessary for residual tumors with high proliferative markers (grade 2b) [11] and/or the aggressive subtypes (WHO 2017) [19].

9.  Temozolomide (TMZ) Treatment

In the past, that is, during the pre-TMZ era, there were no established treatments for aggressive and metastatic PitNETs and the prognosis was poor (mean survival was approximately 2 years) [58-60]. Functioning aggressive PitNETs usually responded poorly to standard medical treatments used for non-aggressive tumors. Surgery may have played a limited role to ameliorate local mass effect such as acute loss of vision or severe intractable headache, or to offer some degree of control over hormone hypersecretion [30].

After the failure of standard therapies, the ESE guidelines recommended using TMZ monotherapy as first-line chemotherapy for aggressive and metastatic PitNETs [30]. It has been shown to improve overall prognosis and achieve progression-free 5-year survival rates in responders [7, 30, 37, 61-65]. TMZ is an alkylating drug with several characteristics including availability in oral form, ability to cross the blood-brain barrier, and generally well-tolerated with low risk of adverse effects. Since the anti-tumor efficacy of TMZ is limited by high level activity of O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, high MGMT immunohistochemical expression is suggestive of a lack of response. Mutations in the genes involved in the DNA mismatch repair (MMR) pathway including MSH6 may also affect the anti-tumor efficacy of TMZ [64]. Nevertheless, there are considerable exceptions [7, 30, 33, 65].

It is recommended to start TMZ treatment for 3 cycles before assessing the initial response. When responding, continue treatment for at least 6 months in total, whereas when non-responding (radiological progression), TMZ treatment should be terminated immediately [30]. Improved response to TMZ therapy was noted in three situations: clinically nonfunctioning tumors, concomitant administration of radiotherapy and low MGMT immunohistochemical expression [61]. Since a high proportion of patients demonstrate tumor progression after TMZ cessation and no other evidence-based treatments are available, a longer duration beyond the commonly used 6–12 months timeframe is recommended if continued therapeutic benefit is observed [31, 61]. The question of the ideal length of TMZ therapy remains open for future exploration.

On the other hand, TMZ is generally well-tolerated, but myelosuppression has been reported in 31% of the patients [65]. Frequently, a dose reduction or delay in treatment cycles can allow the patient to continue treatments [31, 65]. Hematological malignancies have also been reported after many years of TMZ treatment, but the absolute risk is very low [31].

Despite encouraging initial results, recent studies have disclosed that TMZ treatment leads to complete or partial radiological response in only one-third of the patients and does not provide long-term control of aggressive PitNETs in many patients [7, 31]. In addition, TMZ therapy is not covered by the national insurance for treatment of aggressive and metastatic PitNETs in the majority of countries including Japan.

10.  Alternative Treatments for TMZ-resistant Tumors

At this point, no other evidence-based treatments are available for aggressive and metastatic PitNETs. The ESE guidelines recommend a trial with other systemic cytotoxic therapies but are unable to suggest a particular regimen [30]. Historically a variety of cytotoxic drugs, including lomustine (CCNU), 5-FU, and so on, have been used but did not provide long-term control [58].

Some case reports have suggested that other medications might be useful in combination with TMZ. These include TMZ and capecitabine [66, 67], bevacizumab, thalidomide, and BCNU. VEGF-targeted therapy (bevacizumab) has been tried as monotherapy and in combination with TMZ with some degree of success in a few patients [27, 68].

As described for other NETs, peptide receptor radionucleotide therapy (PRRT), mainly radiolabelled somatostatin analogues, could be an alternative option for tumors resistant to TMZ [29, 31, 69, 70].

The newest therapeutic option to be studied in aggressive and metastatic PitNETs are immune-checkpoint inhibitors (ICIs). Radiological responses have been reported in some cases treated with combined ipilimumab and nivolumab [71, 72]. Future possibilities to improve ICI efficacy include combining ICIs with radiotherapy or with drugs that target angiogenesis [31].

11.  Conclusions

Aggressive PitNETs are heterogenous tumors that are often difficult to predict and mostly difficult to manage. In general, they are invasive and proliferative tumors with early and frequent recurrences, resistant to conventional treatments and without metastases. No single morphological or histological marker has been shown as yet to reliably predict their aggressive behavior. At present, the identification of potentially aggressive PitNETs should be made on an individual basis by considering the tumor subtype, proliferative potential, and tumor invasion assessment.

In terms of treatment, TMZ had been considered promising and the sole therapeutic option for aggressive and metastatic PitNETs. However, recent reports have disclosed that fewer than half of the patients respond to TMZ, and that TMZ does not provide long-term control of many aggressive PitNETs. It is necessary to establish a further multidisciplinary approach for both reliable prediction and successful management of aggressive PitNETs.

Disclosure

I have no potential conflicts of interest associated with this research.

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