Among a total of 93 cases of APT/PC corticoPiT (47.3% APT and 48.4% PC, 4.3% either APT or PC), 59.1% (n = 55) were men (M) [4, 20, 23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52] and 40.9% (n = 38) women (W) [4, 27, 28, 34,35,36,37,38, 42, 48, 52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70] (Supplementary Table 1). Relevant clinical and pathological data are summarised in Table 1.

A male predominance was observed in both APT and PC. Median follow-up from diagnosis was similar both sexes (Table 1). Age at diagnosis was comparable between sexes, with a median of 47 years (IQR 38.5–54.5) in men and 45 years (IQR 40.0–53.0) in women. Metastases occurred at a median age of 56 years (IQR 50.0–64.4) in men and slightly earlier in women, without statistical significance. In women the most common metastases localisation was the liver, whereas in men, they more frequently involved bones.

Functioning (F) tumours at diagnosis were 82.4% in women and 63.5% in men (Table 1); whereas non-functioning (NF), or silent, corticoPiT at diagnosis were observed mainly in men, accounting for 36.5% of cases (n = 19/52), compared with 17.6% in women (n = 6/34). All the NF cases had a histological diagnosis of corticoPiT. A shift from NF to F was observed in both sexes: 5 cases in women and 9 cases in men. Conversely, loss of secretory activity occurred exclusively in men (Table 1). Functioning status changed before evidence of overt aggressiveness in 4 men and one woman: from NF to F in 3 patients (1 W and 2 M), and from F to NF in 2 men. In 6 cases (4 M and 2 W) this shift happened either when the tumour was already recognised as aggressive or at the same time of evidence of aggressiveness: 3 men and 2 women shifted from NF to F, and one man from F to NF. For the remaining patients timing could not be established.

Data on tumour volume at diagnosis was available only for 40.0% of men and 55.3% of women. In both sexes, the majority were macrotumours (dmax ≥ 1 cm), identified in 95.5% of M and 76.2% of W (Table 1); giant tumours (dmax ≥ 4 cm) were rare: reported in 1/22 man and 2/21 women. Interestingly, microtumours (dmax < 1 cm) at initial presentation were observed exclusively in women, representing 14.3% (n = 3/21, 2 PC and 1 APT) of cases with available information. In one case [58], severe treatment-resistant Cushing’s disease, progressed to overt tumour growth and metastases following bilateral adrenalectomy. In another patient [57] rapid progression occurred in a tumour with a high proliferative index (Ki-67 = 40%) after initial surgery and severe hypercortisolism at initial presentation. In the third case [55], tumour recurrence after initial surgery showed a transition from densely to sparsely granulated corticoPiT, which is associated with aggressiveness [71]. These observations indicate that, especially in women where microadenomas are more common, even small lesions may undergo aggressive or malignant evolution, highlighting the need for careful follow-up.

Data on radiological tumour invasion at clinical presentation or prior to any treatment are limited. Among cases with available information, invasion was reported in 73.3% of women and in 100% of men, a difference that was statistically significant (p: 0.03) (Table 1). In 10 cases (4 M and 6 W), invasion developed when aggressive behaviour was more evident: 2 of them were not invasive at first presentation, and for the remaining 8 this information was not available. In total, 90.0% of women and 100% of men had invasive tumour at initial diagnosis and after evidence of aggressiveness (Table 1).

First line treatment was pituitary surgery for the vast majority of women and men; 2 patients (1 M and 1 W) were treated with steroidogenesis inhibitors first, and one woman received chemotherapy due to a misdiagnosis (Table 1). All patients underwent at least one pituitary surgery, except for one woman who had a biopsy followed by other lines of treatment [38], and 4 patients (3 women and 1 man) for whom surgical information was missing [52]. Postoperative radiotherapy was administered in 93.3% of patients (Table 1), and it always preceded the evidence of aggressive behaviour, except for 3 tumours which were diagnosed as APT/PC at diagnosis [24, 47, 48, 62]. Conventional medical treatment with adrenal steroidogenesis inhibitors and/or pasireotide was administered in about one third of patients, without significant differences between sexes (Table 1).

Bilateral adrenalectomy (BADX) to control refractory hypercortisolism was performed in similar proportion of men (46.3%) and women (50.0%) (Table 1). In 14 patients (8 W and 6 M) it was performed before the onset of overt aggressiveness, while in 11 (5 W and 6 M) it was performed after the diagnosis of aggressive/malignant behaviour. This information was not available for the remaining 9 patients (2 W and 7 M). Corticotroph tumour progression after BADX, formerly known as Nelson’s syndrome, was observed in 66.7% of women and 47.4% of men without statistical significance (Table 1). In 4 cases (2 M and 2 W) tumour progression occurred in an already defined aggressive disease (after TMZ in 2 cases), while in 11 (4 M and 7 W) it happened before or at the time of evidence of aggressive behaviour.

No patient received adjuvant treatment after BADX. However, in one man [33] neoadjuvant RT was performed before BADX while he was undergoing TMZ treatment and it possibly prevented further disease progression. Additionally, one woman without previous BADX showed tumour progression [60], likely due to mitotane-induced adrenolysis.

Pathological information was limited. In corticoPiT, the Crooke’s cell subtype, diagnosed on the presence of hyaline changes, is considered aggressive [71]. It was significantly more frequent in women than in men (p: 0.006) (Table 1), and all information was retrieved by samples before the evidence of aggressive behaviour.

Ki-67 index, a proliferative marker associated with tumour behaviour in APT/PC cohorts [2, 3], was assessed on the primary tumour in 68.8% (n = 64) of patients. For 3 patients (2 men and 1 woman) only categorical information (low vs. high) was reported. At the first available surgery, values of Ki-67 ≥ 3% and Ki-67 ≥ 10% were observed in similar proportion of men and women, with no significant difference (Table 1).

For 29/64 (17 M and 12 W) patients with available Ki-67 it was possible to assess Ki-67 values before and/or after the evidence of aggressive or malignant behaviour. Detailed information can be found in Table 1. No relevant differences were found between sexes both at initial presentation and after evidence of aggressiveness. It was possible to evaluate the Ki-67 trend for only 8 patients: in 5 (2 W and 3 M) it increased in subsequent surgeries and reached levels higher than 10% in all, while it decreased in 3 (2 W and 1 M) to levels of 5 and 1%. These data suggest that Crooke cell tumours, considered a morphologic feature of aggressiveness, are more frequent in women, while Ki-67 index was not significantly different between sexes. The other markers of aggressiveness (p53 and number of mitoses) were available for very few cases and therefore they will not be reported. Proliferative tumours, according to the Trouillas’ classification [72] could be identified in 89.5% of men (n = 17/19) and 81.8% of women (n = 9/11) at first available surgery, without significant difference.

Trouillas’ grade could not be assessed due to the very low number of patients for whom information on both invasion and proliferative markers was available.

Across all the studies, 21.9% (n = 16/73) deaths were registered which corresponded to an identical mortality rate in both sexes and time to death from diagnosis was similar in men and women (Table 1). However, outcome data were missing for 14 men and 6 women.

Temozolomide was administered as first-line non-standard treatment in 100% of men and in 91.7% of women with available data on treatment regimen (Table 1). Following disease progression on TMZ, additional therapeutic options were employed: ICIs (pembrolizumab, nivolumab and ipilimumab) and bevacizumab (BVZ) were the most common, while chemotherapy, mTOR inhibitor everolimus and PRRT were used in a minority of patients (Table 1).

Tumour and hormonal responses to temozolomide treatment are shown in Fig. 1 and best tumour and hormonal responses for each patient are showed in Supplementary Table 2.

Best tumour and hormonal response to temozolomide treatment according to sex in corticoPiT. (a) Tumour responses. Men: CR: 9.1%, PR: 42.4%, SD: 33.3%, PD: 15.1%; women: CR: 25.0% in PR: 35.0%, SD: 25.0%, PD: 15.0%. (b) Hormonal responses. Men: CR 38.1%, PR: 42.8%, SD: 0%, PD: 18.1%; women: CR 57.1%, PR: 21.4%, SD: 7.2%, PD: 14.3%. Tumour and hormonal responses are established according to the RECIST criteria for solid tumours. The number of responders is expressed in percentage (%) of patients with available information. Abbreviations: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease

Tumour complete response (CR) was observed in 22.2% (n = 6/27) of women and 4 of them showed associated hormonal CR. CR was sustained in 83.3% (5/6) at last follow-up (median 27.5 months, IQR 22.5–50.5). In men, 9.1% of tumour CR (n = 4/44) were reported and concordant hormonal CR was seen in 75% of those with tumour CR (n = 3/4). These responses were mainly obtained on TMZ treatment (Fig. 1) All men tumour CR and concordant hormonal responses were sustained (Supplementary Table 2) at last follow-up (median 42.5 months, IQR 33.7–48.7).

Best tumour response was partial response (PR) in 37.0% of women (n = 10/27). Associated hormonal responses were: 5 CR and 3 PR. In 2 patients with initial PR, disease finally progressed; while in one with initial associated hormonal CR a mild biochemical progression was seen that led to a final PR when final hormonal values were compared with pre-treatment ones (Supplementary Table 2).

Tumour PR was described in 40.9% of men (n = 18/44) and concordant hormonal PR was observed in 4 cases. In 7 patients hormonal CR was recorded, instead. Metastatic disease developed or progressed in 4 men during or after the completion of treatment, despite an initial tumour PR (Supplementary Table 2). Both tumour and hormonal progression were observed after initial PR or CR in 3 patients, while only tumour progression was observed in one patient with initial PR and hormonal CR.

Of note, in some cases only general description of treatment response was available and they were excluded by the treatment response evaluation. In 2 patients (one woman and one man) tumours were reported to be “responsive” to temozolomide treatment [34]; one man was reported to be “free from tumour progression and metastases” [44]; normal cortisol levels after temozolomide were described in one woman [62].

Stable disease (SD) as best tumour response was observed in 25.9% of women (n = 7/27). One patient had a concordant hormonal SD, whereas 3 of them showed better hormonal than tumour response: 2 were PR and one was a CR. Among women with SD, one progressed after TMZ, and one showed a better response on metastases (PR) than on primary tumour after TMZ (Supplementary Table 2).

In men, tumour SD as best response was reported in 36.4% (n = 16/44). Seven hormonal responses were available, and they were all better than tumour response: 2 were CR and 5 were PR. Four patients showed tumour progression, in one case accompanied by hormonal progression, after initial response. In one patient instead, tumour remained stable despite hormonal progression.

Hormonal SD only was observed in one further patient (man), while his tumour never responded to treatments. Hormonal SD was not sustained in this case, and the patient eventually progressed.

Focusing on hormonal responses: 19 were available in women and 27 in men. CR were 52.6% in women (n = 10) and 44.4% in men (n = 12); PR were 26.3% in women (n = 5) and 37.5% in men (n = 9), SD were one in women and one in men.

Among women, 4 patients (4/27, 14.8%) never responded to any treatment and tumour progression was associated with hormonal progression in four of them (information was not available for one); 6 tumours in men (6/44, 13.7%) always progressed despite treatments. One of these cases showed initial and not sustained hormonal SD, as discussed earlier. The remaining 5 have always shown hormonal progressive disease.

In women it may seem that there is a tendency to higher tumour CR with respect to men (22.2% vs. 9.1%), but this was not confirmed by ꭓ2 test. No relevant differences were found concerning hormonal responses. Final tumour and hormonal PD were observed in similar proportion of men (29.5% for tumour and 33.3% for hormones) and women (29.6% for tumour and 31.5% for hormones) and no statistical difference was found. In general tumour and hormonal responses were concordant and positive tumour responses were associated with an equal or better hormonal response.

A total of 80 patients with lactoPiT were included, comprising of 47.5% (n = 38) APTs and 52.5% (n = 42) PCs. Among them, 63.8% were men [28, 34, 38, 42, 52, 73,74,75,76,