Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET)

Various complications of pituitary neuroendocrine tumors (PitNET) are reported, and an intratumor hemorrhage or infarct underlying pituitary apoplexy (PA) represents an uncommon, yet potentially life-threatening, feature, and thus early recognition and prompt intervention are important. Our purpose is to overview PA from clinical presentation to management and outcome. This is a narrative review of the English-language, PubMed-based original articles from 2012 to 2022 concerning PA, with the exception of pregnancy- and COVID-19-associated PA, and non-spontaneous PA (prior specific therapy for PitNET). We identified 194 original papers including 1452 patients with PA (926 males, 525 females, and one transgender male; a male-to-female ratio of 1.76; mean age at PA diagnostic of 50.52 years, the youngest being 9, the oldest being 85). Clinical presentation included severe headache in the majority of cases (but some exceptions are registered, as well); neuro-ophthalmic panel with nausea and vomiting, meningism, and cerebral ischemia; respectively, decreased visual acuity to complete blindness in two cases; visual field defects: hemianopia, cranial nerve palsies manifesting as diplopia in the majority, followed by ptosis and ophthalmoplegia (most frequent cranial nerve affected was the oculomotor nerve, and, rarely, abducens and trochlear); proptosis (N = 2 cases). Risk factors are high blood pressure followed by diabetes mellitus as the main elements. Qualitative analysis also pointed out infections, trauma, hematologic conditions (thrombocytopenia, polycythemia), Takotsubo cardiomyopathy, and T3 thyrotoxicosis. Iatrogenic elements may be classified into three main categories: medication, diagnostic tests and techniques, and surgical procedures. The first group is dominated by anticoagulant and antiplatelet drugs; additionally, at a low level of statistical evidence, we mention androgen deprivation therapy for prostate cancer, chemotherapy, thyroxine therapy, oral contraceptives, and phosphodiesterase 5 inhibitors. The second category includes a dexamethasone suppression test, clomiphene use, combined endocrine stimulation tests, and a regadenoson myocardial perfusion scan. The third category involves major surgery, laparoscopic surgery, coronary artery bypass surgery, mitral valvuloplasty, endonasal surgery, and lumbar fusion surgery in a prone position. PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short- and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to neurosurgical decisions and their timing versus conservative approach. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events, and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture (if any, as seen in subacute PA) and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary.


Clinical Presentation in Cases with PA: Neurologic and Ophthalmic Elements
Sudden headache was the most frequent symptom and occurred in more than two-thirds of patients. (Table 1) Headache was severe, often described as the most painful headache episode an individual has ever experienced, and graded, for example, as high as 9 on a scale from 0 to 10, with 10 being the most severe in one study [31]. For practical purposes we point out that headache was absent in some cases; thus, an index of suspicion should be provided by other endocrine and non-endocrine clinical elements [43,86,. For instance, Enatsu et al. reported a 65-year-old woman admitted for a nonfunctioning pituitary adenoma-associated PA who presented third cranial nerve

Clinical Presentation in Cases with PA: Neurologic and Ophthalmic Elements
Sudden headache was the most frequent symptom and occurred in more than twothirds of patients. (Table 1) Headache was severe, often described as the most painful headache episode an individual has ever experienced, and graded, for example, as high as 9 on a scale from 0 to 10, with 10 being the most severe in one study [31]. For practical purposes we point out that headache was absent in some cases; thus, an index of suspicion should be provided by other endocrine and non-endocrine clinical elements [43,86,. For instance, Enatsu et al. reported a 65-year-old woman admitted for a nonfunctioning pituitary adenoma-associated PA who presented third cranial nerve palsy and sudden decrease in visual acuity unaccompanied by headache [196]. Another example is a 65year-old male who developed PA as a post-operative complication after a coronary artery surgery; he only presented diplopia and third cranial nerve palsy [214]. Other circumstances without headaches involve a comatose status. The case presented by Bhogal et al. involves a 63-year-old man with bradycardia and hypotension due to myxedema coma as part PAassociate hormonal picture [215]. Elsehety et al. reported a 60-year-old woman with vision loss and progression to coma due to an acute stroke as a surrounding event to PA [216].
Other common symptoms include nausea and vomiting, either with a neurological or endocrine component (acute secondary adrenal insufficiency) [25,29,30,33,174,176,217]. As mentioned, altered consciousness of various degrees up to coma was identified in 24 papers [56,64,70,79,93,97,100,103,111,112,114,122,123,141,151,169,174,177,189,209,210,215,216,218]. Weakness as a distinct clinical element was specified in five clinical cases (as a neurologic or endocrine consequence) [73,147,188,202,217].
Another important clinical finding is meningism, a crucial clue for differentiating between two life-threatening conditions: PA presenting as aseptic meningitis and bacterial meningitis. PA mimics neurological conditions, such as bacterial [30,37,39,59,63,78,83,106,119,168] or aseptic [100,176] meningitis, making differential diagnosis difficult. Both PA and meningitis share a similar clinical presentation with nuchal rigidity [30,59,70,78,83,119,168], positive Kernig and Brudzinski signs [37,78], fever [30,59,78,83], photophobia [39,70,83], and altered states of consciousness [30,83,106,176]. Moreover, laboratory findings consistent with bacterial meningitis, such as neutrophilic pleocytosis [30,39,59,78,119,176], and high protein content [39,59,83,119,176] were also observed in PA. In terms of glucose content of cerebrospinal fluid (CSF), patients presented with normal [59,78,83,119] or high [176] levels in CSF. In spite of findings suggestive of bacterial meningitis, all CSF cultures were sterile [30,39,59,78,83,100,119,176]. In one case, differential diagnosis was particularly difficult [78]. Villar-Taibo et al. presented a patient with clinical presentation (nuchal rigidity, positive Kernig and Brudzinski signs, and fever) and CSF analyses consistent with bacterial meningitis, whose state improved under antibiotics. Following this event, the subject was diagnosed with PA based on MRI findings and pathological examination. The authors hypothesized that meningitis might have led to PA due to vasculitis. However, it remained unclear whether PA mimicked meningitis or if previous meningitis led to PA [78]. Considering that both PA and bacterial meningitis can be life-threatening, prompt differential diagnosis and treatment are essential. Current findings suggest that the presentation of a clinical picture suggestive of meningitis includes differential diagnosis with PA, especially in patients with sterile CSF, knowing that PA may cause aseptic, irritant chemical, bacterial-like meningitis [39].
PA may associate cerebral ischemia through either extrinsic compression or vasospasm, leading to neurological deterioration (mental status changes, motor deficits, speech impairment) in patients who suffered from acute ischemic stroke following PA [79,107,146,199].

PA and Hormonal Imbalance at First Diagnostic
Endocrine features in subjects admitted for PA include PitNETs-associated hormonal excess, even though most patients were nonfunctioning tumors, respectively, tumor-or PA-caused hypopituitarism (as mentioned, we did not include patients with previously recognized and treated PitNETs). In terms of clinical presentation, Cushingoid features (corticotroph PitNET) are reported in 5 studies (less than 0.005% of the patients): two males of 30, respective 33 years [31,186], a cases series of 4 females aged between 26 and 45 years [33], and other two women of 35, respective 47 years [86,161]. Acromegaly (caused by somatotroph or lactosomatotroph PitNET) was recognized in 8 patients (0.005%) aged between 26 and 50 years; a male [86,109,136,148,156,217] to female [38,78] ratio of 6 to 2. One case of gigantism (+5 SD) was reported on a 9-year-old boy with lactosomatotroph PitNET [32]. Hypopituitarism included elements of hypogonadism [127][128][129]131,135] like disturbances of menstrual cycle in women of reproductive age [171,172], etc., but, also, with a more severe potential, hypotension [29,48,83,199,210,213].

Potential Triggers and Circumstantial Events of PA
Our decade-based analysis showed that high blood pressure may be regarded as the most frequent co-morbidity (or risk factor) followed by diabetes mellitus in individuals admitted for PA. (Table 1) Two cases reported severe, complicated diabetes with diabetic ketoacidosis [53,171,172], and chronic kidney failure [59]. Another endocrine contributor was T3 thyrotoxicosis in one patient [71].
Infectious triggers were also found and include pituitary fungal infection [144], dengue hemorrhagic fever [42,74,77,103,139], varicella [208], and leptospirosis [163]. Of note, Catarino et al. presented the case of a 55-year-old woman who suffered from a corticotroph PitNET-associated PA in relationship to a fungal infection that was surgically treated without anti-fungal treatment [144]. Dengue hemorrhagic fever led to PA in five patients. The underlying mechanism is thrombocytopenia which favors bleeding at the level of PitNET. All patients had pituitary adenomas, with one corticotroph PitNET [103], one somatotroph PitNET [42], and one lactotroph-gonadotroph PitNET [77]. Three patients underwent transsphenoidal surgery (TSS) [42,74,103], one patient was treated conservatively [139], and another patient underwent TSS after initial conservative treatment with cabergoline and dexamethasone due to visual deterioration [77]. The 56-year-old patient introduced by Gohil et al. presented leptospirosis; the proposed mechanisms through which leptospirosis might induce PA include non-inflammatory vasculopathy, as well as platelet dysfunction, rather than thrombocytopenia [163]. An interesting finding was conducted by Humphreys G et al., who analyzed in a prospective study the sphenoid sinus mucosal microbiota characteristics in 10 patients with PA. The authors observed abnormal sinus bacteria like Enterobacteriaceae in patients with PA [105].
Oral contraceptives may contribute to PA [54]. Kobayashi et al. presented a 33-yearold female with ischemic PA of a nonfunctioning macroadenoma following the use of oral contraceptives for 1.5 years. The patient fully recovered under conservative treatment with analgesics and hormone replacement with hydrocortisone and thyroxine. The hypercoagulable state induced by estrogens was hypothesized as an underlying mechanism of PA [54]. Additionally, a vardenafil-triggered PA was reported [140]. Uneda et al. reported a 51-year-old male with signs and symptoms of PA (severe headache and oculomotor nerve palsy) the morning after taking vardenafil for erectile dysfunction for the first time in three months. He was diagnosed with apoplexy of a pituitary adenoma based on CT and MRI findings and was surgically treated. Even though the underlying mechanisms remain unclear, possible mechanisms of PA under phosphodiesterase 5 (PDE) inhibitors are hypotension, vasodilation, and antiplatelet effects [140].
Two case reports presented individuals with PA caused by exposure to high altitudes (the first case was published in 2012). Both subjects were 29-year-old males without underlying pituitary conditions who ascended slowly to altitudes of over 4500 m. The initial diagnosis was acute mountain sickness in both cases. However, due to low blood pressure and findings of adrenal insufficiency, PA was suspected, and later MRI scans confirmed PA. Neither patient displayed visual disturbances [29,48]. The management included transfer to a lower altitude (as a specific approach in this distinct type of PA) as well as glucocorticoid replacements (100 mg of hydrocortisone every eight hours, the first two days, followed by 7.5 mg of prednisolone daily due to persistent hypocortisolism [29], respective 100 mg of hydrocortisone every six hours followed by full recovery [48]. Of note, two unusual triggers are polysubstance abuse [191] and long restraint in a sitting position [221]. The patient presented by Sun et al., a 49-year-old male, died in custody due to a gonadotroph PitNET-associated PA following restraint in a sitting position for four days [221] (Figure 2).

PA Management
The management of the patients recognized with PA is summarized in Table 2. Essentially, the subjects were managed surgically (80%) or conservatively. Although the majority are TSSs, five papers introduced patients undergoing craniotomies [36,60,127,159,217]. Craniotomies were necessary for intracranial hemorrhage [36], subarachnoid hemorrhage [60], previous nasal surgery [127], and technical challenges such as cavernous sinus invasion with encasement of the internal carotid artery [159], respectively, encasing of both carotid arteries [217]. Table 2. Management and outcome in patients PitNET-PA .
Conservative management [218][219][220] included vital signs monitoring, hydroelectrolytic balance, glucocorticoid substitution (intravenous hydrocortisone during the first 48 h followed by oral replacement), as well as substitution with levothyroxine and desmopressin (if needed) [123,168]. A management decision was based on the severity of clinical presentation and progression of the neurologic, eye, and hormonal features. The patients analyzed by Marx et al. were treated surgically when they presented severe visual acuity decrease, worsening of ophthalmological symptoms, resistant headache, or altered consciousness [168]. Similar criteria were applied by Almeida et al. and Bujawansa et al. [66,123]. Clinically stable individuals remained under a conservative approach [66,123,168], as well as subjects to contraindications for performing neurosurgery [123] or those refusing it [218].
A few cases under the "wait and see" approach were later referred to TSS due to worsening conditions: hematoma expansion [51] or sudden visual deterioration [77,158].
We identified three clinically relevant studies that compared conservative management versus TSS in terms of evolution [123,160,168]. Almeida et al. found that visual, cranial nerve, and endocrine outcomes are similar between the two subgroups [123]. Cavalli et al. analyzed the clinical presentation, surgical methods, and treatment outcomes of patients with PA. The authors advocated for conservative management in patients without visual impairment and suggested that a tumor with a vertical diameter greater than 35 mm should be referred to neurosurgery in the presence of visual deficits. The only statistical difference between surgically treated patients and patients under conservative treatment was the higher ratio of achieving resolution of visual field defects at the latest follow-up in the group who underwent emergency surgery [160]. Marx et al. found that following surgery, a higher number of patients presented adrenal insufficiency and hypogonadotropic hypogonadism than those who were managed conservatively, but no statistically significant difference was identified in terms of visual acuity and visual field consequences [168]. Bujawansa S et al. suggested conservative treatment as a safe and adequate approach for selected patients (those with mild and non-progressive neuro-ophthalmic defects) [66]. The findings suggest that surgical treatment wields a higher risk of associating endocrine deficiencies [168], but a higher ratio of visual field defects improvement [161], but with similar outcomes in terms of visual acuity [123,160,168].
We mention some isolated reports with uncommon management such as radiotherapy for a subject diagnosed with a null cell tumor and a gonadotroph PitNET [105]; palliative care with dexamethasone and brain radiotherapy for an individual diagnosed with bronchogenic carcinoma metastases-associated PA [73]; transfer to a lower altitude, as prior mentioned, in specific cases with climbing-induced PA [29,48]; for an intraorbitalinduced PA, the patient was offered orbital surgery, preceded by embolization through direct puncture techniques combined with a transarterial approach via the right ophthalmic artery [206]. Additionally, functional PitNET continued medical therapy for specific hormonal excess with cabergoline [75,77,168,170,199,218] or somatostatin analogs [76]. two days, followed by 7.5 mg of prednisolone daily due to persistent hypocortisolism [29], respective 100 mg of hydrocortisone every six hours followed by full recovery [48].
Of note, two unusual triggers are polysubstance abuse [191] and long restraint in a sitting position [221]. The patient presented by Sun et al., a 49-year-old male, died in custody due to a gonadotroph PitNET-associated PA following restraint in a sitting position for four days [221] (Figure 2).

PA Management
The management of the patients recognized with PA is summarized in Table 2. Essentially, the subjects were managed surgically (80%) or conservatively. Although the majority are TSSs, five papers introduced patients undergoing craniotomies [36,60,127,159,217]. Craniotomies were necessary for intracranial hemorrhage [36], subarachnoid hemorrhage [60], previous nasal surgery [127], and technical challenges such as cavernous sinus invasion with encasement of the internal carotid artery [159], respectively, encasing of both carotid arteries [217].
Conservative management [218][219][220] included vital signs monitoring, hydro-electrolytic balance, glucocorticoid substitution (intravenous hydrocortisone during the first 48 h followed by oral replacement), as well as substitution with levothyroxine
As mentioned, some small studies evaluated the outcome in terms of conservative versus neurosurgical management. A retrospective study (N = 46 patients with PA) showed that individuals with non-severe neuro-ophthalmological deficits were treated conservatively (N = 27), whereas the patients with a pituitary apoplexy score (PAS) ≥4 were treated surgically (N = 19); the only statistically significant difference regarding the outcome was the higher rate of hormonal deficits in the second group [168]. Another study included 49 subjects who were referred for neurosurgery and 18 patients who were conservatively managed and showed similar improvement in visual and cranial nerve palsies [123]. A retrospective study (N = 24 subjects who underwent TSS) showed a complete tumor resection in 87.5% of cases; 94.44% of patients experienced an improvement of visual acuity; diabetes insipidus developed in 16.66% of individuals [174].
The timing of surgery was also taken into consideration by some studies, as a contributor to PA outcome. A study conducted by Rutkowski M et al. (N = 32 patients with acute PA who underwent TSS) included two groups depending on surgery timing: within 72 h of symptom onset and after 72 h; the second group had a statistically significant higher prevalence of hypopituitarism at presentation. However, in terms of hypopituitarism and visual dysfunction recovery, the outcome was similar [121].
The spontaneous resolution of PitNET through PA was reported with a favorable outcome [87,126,154,220]. Ghalaenovi [154]. Tumor resolution with empty sella following conservative management was reported by Saberifard et al. [87].
Of note, we identified through our analysis a single case of PA in the transgender population: a 46-year-old transgender male under testosterone therapy for 3 years who was admitted for severe headache, central hypocortisolism, and hypothyroidism. IGF-1 (insulin-like growth factor) levels, however, were high. The patient was diagnosed with somatotroph PitNET-associated PA and received surgical treatment with normalization of IGF-1 and improvement of secondary diabetes mellitus. Particularly, testosterone therapy in this situation may mask acromegaly features [76] (please see Table 2).

Subentities concerning PA
An unusual case of "pneumo-apoplexy" was described by Singhal A et al.; a 65-yearold female had a PA-associated hemorrhage accompanied by pneumosella and manifested as rhinorrhea as well as classical symptoms of PA including headache and visual loss. The patient needed flap replacement of the nasoseptal defect [137].
"Recurrent" apoplexy was reported by Hosmann A et al. in 4 out of 76 patients (5.3%) after initial neurosurgery. Potential factors include residual post-operatory tumor, cavernous sinus invasion of PitNET, and ophthalmoplegia [128]. However, a recurrent tumor after initial TSS due to PA-PitNET may be found as seen in the general population with PitNET who were previously candidates for neurosurgery [145,168]. Some patients presented "subacute" PA, with little to no symptoms, thus the importance of imaging assessments like MRI scans that point out infarction or hemorrhage [166]. The term "subacute" is used for PA associated with clinical symptoms less severe than fully manifested (or "acute") PA, thus the importance of awareness since many cases may be under-diagnosed [166,222]. Iqbal F et al. published a retrospective analysis on 55 patients (33 with acute PA and 22 with subacute PA). Severe headache and hyponatremia were more frequent in the acute group whereas the ratio of individuals who were referred to surgery was similar between the two subgroups [166]. Garg M et al. described the case of a 22-year-old female with vision reduction as the single symptom [197]. Klimko A et al. also reported a 41-year-old acromegalic male with subacute PA and panhypopituitarism [148].

Controversies in PA Domain
PA is an emergency that typically presents a sudden and severe headache and visual symptoms; however, subacute cases or those without headaches should not be missed. The most frequent cause is hemorrhage or ischemia in a nonfunctioning pituitary adenoma, but hormonally active PitNET may embrace a PA scenario. Middle-aged males are affected with the highest frequency, but both pediatric and elderly cases are shown in Table 1. The most common risk factors are high blood pressure, diabetes mellitus, and anticoagulation/antiplatelet therapy; however, at the level of case reports, uncommon conditions are reported as we prior pointed out. (Table 1) Differential diagnosis is sometimes crucial, as PA can mimic a number of conditions including meningitis or temporal arteritis [134]. Controversies around the exact panel of PA contributors still exist since there are still pathogenic elements that remain unclear. Whether the mentioned comorbidities as displayed in Figure 1 are directly connected to PA or are incidental is still a matter of debate.
The optimal treatment approach remains debated, but the main treatment options are TSS or conservative management. Due to possible complications from surgery, as well as a higher rate of pituitary insufficiencies after surgical treatment when compared with conservative management, careful evaluation is necessary. The individual multidisciplinary decision is mandatory. Surgical management should be reserved for patients with visual impairment due to cranial nerve palsies and optic chiasm compression, or patients with other neurological deficits. Conservative treatment is usually an adequate approach for stable patients with mild and stationary visual deficits and without further neurological impairments. When choosing conservative management, the risk of PA recurrence should also be taken into account. (Figure 3).
In terms of outcome, headaches and visual disturbances may resolve following both conservative and surgical treatment. Patients can present different degrees of anterior hypopituitarism and diabetes insipidus. Factors for a worse prognosis may be the presence of a large macroadenoma and an ischemic type of apoplexy. PA is a condition that can lead to a favorable outcome with the remission of symptoms and underlying pituitary disorder in some patients, whereas for others it can be life-threatening and invalidating when fatal cases are reported (as we already mentioned). Specific algorithms of management are still necessary.
To our knowledge, this is the largest analysis of published cases concerning spontaneous PA (outside pregnancy and COVID-19 infection). A timeline of published papers from 2012 to 2022 according to our methodology is displayed below. The largest studies addressing individuals with PA included 109, 97, and 87 subjects, respectively .
(please see Tables 1 and 3 and Figure 4) Table 3. Retrospective studies with minimum 10 patients confirmed with PA/study according to our methodology [25,66,70,90,100,[111][112][113]120,121,123,128,141,151,160,162,166,168,169,174,[181][182][183].   Figure 3. Imaging capture of a pituitary apoplexy. This is a male patient in his late 20s diagnosed with pituitary apoplexy with no prior medical or surgical history. On first presentation as an outpatient (due to severe headache), magnetic resonance imaging (performed as an emergency) shows a pituitary mass of 2.5 cm maximum diameter with inhomogeneous pattern suggesting hemorrhage (yellow arrow) at the level of a pituitary tumor (left). Intravenous contrast computed tomography (10 months since transsphenoidal surgery) shows a tendency to empty sella and no tumor remnants (yellow arrow) at the same level (right). Both captures are coronal plane.

Author
In terms of outcome, headaches and visual disturbances may resolve following both conservative and surgical treatment. Patients can present different degrees of anterior hypopituitarism and diabetes insipidus. Factors for a worse prognosis may be the presence of a large macroadenoma and an ischemic type of apoplexy. PA is a condition that can lead to a favorable outcome with the remission of symptoms and underlying pituitary disorder in some patients, whereas for others it can be life-threatening and invalidating when fatal cases are reported (as we already mentioned). Specific algorithms of management are still necessary.
To our knowledge, this is the largest analysis of published cases concerning spontaneous PA (outside pregnancy and COVID-19 infection). A timeline of published papers from 2012 to 2022 according to our methodology is displayed below. The largest studies addressing individuals with PA included 109, 97, and 87 subjects, respectively .
(please see Tables 1 and 3 and Figure 4) Figure 3. Imaging capture of a pituitary apoplexy. This is a male patient in his late 20s diagnosed with pituitary apoplexy with no prior medical or surgical history. On first presentation as an outpatient (due to severe headache), magnetic resonance imaging (performed as an emergency) shows a pituitary mass of 2.5 cm maximum diameter with inhomogeneous pattern suggesting hemorrhage (yellow arrow) at the level of a pituitary tumor (left). Intravenous contrast computed tomography (10 months since transsphenoidal surgery) shows a tendency to empty sella and no tumor remnants (yellow arrow) at the same level (right). Both captures are coronal plane.   Table 1).
Abbreviations: N represents the number of patients included in studies with at least 10 subjects with PA per article (of note: in Table 1 we used the term "case series" or "study" according to the original publication; in this figure, we strictly included the original research depending on the number of patients). Abbreviations: N represents the number of patients included in studies with at least 10 subjects with PA per article (of note: in Table 1 we used the term "case series" or "study" according to the original publication; in this figure, we strictly included the original research depending on the number of patients).
Notably, PitNETs terminology and associated concepts massively changed since the WHO 2022 classification. Our 10-year analysis included cases with PA in relationship with different tumors that were diagnosed according to the criteria at that time. Recently, "PitNET" replaced "pituitary adenoma" which, however, is still allowed to be used. Grossly, there are three types of tumors arising from the anterior lobe: PitNET, pituitary blastoma, and craniopharyngioma (two specific subtypes). The modern approach of these tumors massively takes into consideration the role of immunohistochemistry for mainly five elements: PIT1, TPIT, SF-1, GATA3, and ERα in order to profile PitNET subtypes. The major changes are, a part form this new terminology: null cell tumors and unclassified pluri-hormonal tumors as a subtype of PitNETs with negative staining for transcription factors; "metastatic" PitNET replaced "metastatic carcinoma" that should be differentiated from a neuroendocrine carcinoma; immature (formerly "silent") or mature PIT1-lineage tumor are determined based on PIT1 immunostaining; and mammosomatotroph, acidophil stem cell tumors in addition to mixed somatotroph/lactotroph tumors are distinct types with respect to PIT-1 lineage of PitNET [223][224][225][226] (Figure 5).

Limitations
We acknowledge that the current review did not follow the PRISMA guidelines for systematic review and may have missed some studies because only PubMed was used for the literature search.

Conclusions
PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short-and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to surgical decisions and their timing. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture (if any, as seen in subacute PA) and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total  [223][224][225][226]. PitNET = pituitary neuroendocrine tumors; * well-differentiated adenohypophyseal tumors (formerly pituitary adenomas); ** two specific subtypes.

Limitations
We acknowledge that the current review did not follow the PRISMA guidelines for systematic review and may have missed some studies because only PubMed was used for the literature search.

Conclusions
PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short-and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to surgical decisions and their timing. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture (if any, as seen in subacute PA) and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary. Acknowledgments: We thank the patient who provided us with the imaging captures from his own personal records.

Conflicts of Interest:
The authors declare no conflict of interest.