Introduction

Pituitary carcinoma is a rare disease, defined by the presence of cerebrospinal or distant metastasis of an adenohypophysial tumor [1, 2]. The vast majority of patients who receive this diagnosis present initially with a pituitary neuroendocrine tumor (PitNET) [3] that has no distinctive features to suggest metastatic potential. The ability to distinguish these carcinomas from other aggressive PitNETs remains a challenge [4].

Only a small number of cases of pituitary carcinoma have been reported in the literature [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. The majority are corticotroph tumors with Cushing disease [42, 43], but tumors of all of the various adenohypophysial cell types have been reported to be malignant. We reviewed our institutional experience with pituitary carcinoma since the publication of a previous case [26].

Materials and Methods

To review our institutional experience of pituitary carcinoma, we searched the database of the UHN Endocrine Oncology Site group and the UHN pathology laboratory information system from 2001 to 2016 with approval of the University Health Network Research Ethics Board. Among 1055 PitNETs from 1169 transsphenoidal resections [46], we identified 4 cases of pituitary carcinoma. Here we describe the clinical and pathologic features and response to management approaches.

Results

The incidence of pituitary carcinoma was approximately 0.4% of all PitNETs. All four patients were women. The age at initial presentation ranged from 23 to 54 years. Two patients had Cushing disease, one had galactorrhea-amenorrhea syndrome, and one had a clinically non-functional poorly differentiated PIT1 lineage tumor. The time from diagnosis of PitNET to the diagnosis of malignancy was 3 to 14 years (mean, 8 years). One patient died of disease 18 years after the initial diagnosis of a PitNET. The others are alive with disease. The details of the four cases are presented (Table 1).

Table 1 Clinical and pathological features of four pituitary carcinomas
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Case 1

A 23-year-old woman presented with a 2.8-cm clinically non-functioning pituitary tumor. She underwent transsphenoidal resection; pathology identified a poorly differentiated PIT1 lineage tumor (formerly known as “silent subtype 3 pituitary adenoma”) that was composed of spindle-shaped and polygonal cells with strong PIT1 positivity, focal ER reactivity, and a Ki67 index of 15% (Fig. 1). There was global loss of nuclear PTEN expression as well as variable loss of nuclear Rb expression, but the tumor cells were positive for p27 and SDHB. There was no p53 overexpression. She had local regrowth and underwent a second transsphenoidal resection prior to the documentation of metastatic disease in the cerebellum and mediastinum 5 years after initial diagnosis (Fig. 1). Therapy with external beam radiotherapy and a number of medical therapies including the combination of capecitabine/temozolomide was unsuccessful and she continues to have disease progression. She was subsequently enrolled in a clinical trial of peptide receptor radionuclide therapy (PRRT).

Fig. 1
figure 1

This patient initially had a sellar mass (a) and underwent two transsphenoidal resections prior to the documentation of metastatic disease in the cerebellum (a, b) and mediastinum (c). The tumor was a poorly differentiated PIT1 lineage tumor that was composed of spindle-shaped and polygonal cells (c, d) with strong PIT1 positivity (e), focal ER reactivity (f), and a Ki67 index of 15% (g)

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Case 2

A 40-year-old woman presented with florid pituitary Cushing disease; MRI (Fig. 2) showed a 6 × 5-mm sellar tumor. She underwent transsphenoidal resection of a densely granulated corticotroph tumor (Fig. 2) with a Ki67 index of 4.7%. Recurrence 7 years later led to a second pituitary surgery and resection showed transition to a sparsely granulated corticotroph tumor consisting of chromophobic or lightly basophilic tumor cells. Both tumors showed strong keratin and variable ACTH positivity. Persistent ACTH excess and Cushing disease failed to respond to somatostatin analog therapy and she required bilateral adrenalectomy. Two years later, she was found to have a liver lesion; a liver biopsy identified metastatic neuroendocrine tumor with cytoplasmic positivity for ACTH and nuclear positivity for TPIT (Fig. 2). This confirmed the diagnosis of pituitary corticotroph carcinoma. Of note, the patient also had a papillary thyroid carcinoma diagnosed shortly before the liver lesion was identified, and she had a well-differentiated L cell appendiceal neuroendocrine tumor (NET) invading the muscularis propria with grade 2 proliferative features (Ki67 16.5%) and no ACTH immunoreactivity 1 year prior to the thyroid carcinoma. This appendiceal NET was assessed for menin, SDHB, and microsatellite instability markers (MSH6, MSH2, MLH1, and PMS2) and all were intact. Menin staining was intact in the pituitary tumor. Stains for p27 (encoded by CDKN1B) were negative in the pituitary lesion, consistent with its functional status [46], but the appendiceal L cell NET was positive for this marker of MEN4. Germline genetic testing for MEN1 yielded no pathogenic alterations.

Fig. 2
figure 2

This patient with Cushing disease had a small intrasellar tumor (a) and subsequently developed liver metastasis (b). The pituitary tumor was initially a basophilic densely granulated corticotroph tumor (c), but at reoperation 7 years later, the recurrent tumor had transitioned to a chromophobic sparsely granulated corticotroph tumor (not shown); both tumors showed strong keratin and variable ACTH positivity (not shown). Persistent ACTH excess and Cushing disease required bilateral adrenalectomy. A liver biopsy identified metastatic neuroendocrine tumor (d) with cytoplasmic positivity for ACTH (e) and nuclear positivity for TPIT (f), confirming the diagnosis of pituitary corticotroph carcinoma. This stain for TPIT was required since the patient also had a well-differentiated L cell appendiceal NET with no ACTH reactivity

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Case 3

A 49-year-old woman presented with Cushing disease for which she had pituitary surgery for a small intrasellar tumor. She underwent a second pituitary resection the next year due to persistent disease. She was referred to our institution with persistent disease (Fig. 3) when she was 60 years old and a third pituitary procedure was performed. This yielded a Crooke cell tumor with a Ki67 labeling index of 10% (Fig. 3). As this third pituitary resection was also unsuccessful in achieving a biochemical remission, she underwent bilateral adrenalectomy. This was followed by the rapid development of Nelson’s syndrome that did not respond to external beam radiation, temozolomide, everolimus, sunitinib, or bevacizumab. In 2009, 14 years after her initial presentation, metastatic lesions in bone were shown on biopsy to represent metastatic corticotroph carcinoma (Fig. 3). She died of wide-spread disease progressive in the brain, liver, and bones at age 67.

Fig. 3
figure 3

This patient had Cushing disease due to a pituitary tumor (a) that was treated with multiple surgeries and bilateral adrenalectomy resulting in Nelson’s syndrome; she ultimately developed metastatic lesions in the liver (b) and bone (c). The tumor was a Crooke cell tumor (d) highlighted with the PAS stain (e) and also identified in a bone biopsy (f); the pituitary tumor was strongly positive for keratins using the CAM 5.2 stain (g) and had a Ki67 labeling index of 10% (h); the bone lesion shows the same pattern of keratins (i) as well as ACTH (not shown), consistent with metastatic Crooke cell tumor

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Case 4

A 54-year-old woman had a 2.5-cm sellar tumor with hyperprolactinemia (729 μg/L; normal range 1.2–29.9) that failed to respond to dopamine agonist therapies. She underwent transsphenoidal surgery. At surgery, the tumor was highly fibrotic and could not be completely resected. The tumor had strong nuclear positivity for PIT1 and ER (Fig. 4); interpretation of the PRL staining was suboptimal due to extensive fibrosis and non-specific background, but there was Golgi pattern accentuation of reactivity, consistent with a sparsely granulated lactotroph tumor. Stains for SF1 and other pituitary hormones were all negative. The Ki67 labeling index was 20% despite medical therapy that would have been expected to reduce proliferation by a lactotroph tumor. A second surgical procedure did not successfully normalize prolactin levels. She then developed tumor in the right fronto-temporal lobe that was biopsied and proved to be metastatic lactotroph carcinoma. She underwent external beam radiation therapy and somatostatin analog therapy. At the age of 60 she developed biopsy-proven metastatic pituitary carcinoma in the L2 vertebral spine. Genetic testing revealed an MEN1:c.1117C>T representing a sequence variant of unknown significance.

Fig. 4
figure 4

This patient had a 2.5-cm sellar tumor and hyperprolactinemia that failed to respond to dopamine agonist therapies; she subsequently developed metastatic lesions in the frontal lobe (a, b) and in the L2 vertebra that had similar morphology to her primary pituitary lesion, a highly fibrotic tumor with strong nuclear positivity for PIT1 (a) and reactivity for ER (b); staining for PRL was suboptimal due to extensive fibrosis and non-specific background (c) but there was Golgi pattern accentuation of reactivity, consistent with a sparsely granulated lactotroph tumor. Stains for SF1 and other pituitary hormones were negative (not shown). The Ki67 was 20% (d)

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Discussion

Our case series indicates that pituitary carcinoma represents approximately 0.4% of all PitNETs. In our series, all patients with pituitary carcinoma were female and the ages at initial presentation ranged from 23 to 54 years; the time to development of metastasis ranged from 3 to 14 years from the initial diagnosis of a PitNET. Apart from a relatively high Ki67 labeling index (≥ 10%) in three tumors, there were no cytomorphologic features at the time of initial presentation that could predict subsequent metastatic behavior.

The pathogenesis of malignant transformation in pituitary carcinoma is unknown. There have been reports of RAS mutations [47, 48]; other studies have suggested alterations in ATRX, PTEN, and Tp53 [45, 49]. Biomarkers that have been applied in diagnosis include galectin-3 [50] and p53 [51] expression as well as loss of Rb [24]. One patient was reported to have Lynch syndrome [38] and another patient was reported to have an SDHB-immunodeficient gonadotroph carcinoma in the context of germline SDHB mutation [39]. High Ki67 labeling indices are a feature of these tumors [52]; however, not all PitNETs with high Ki67 labeling indices progress to pituitary carcinoma. A meta-analysis published in 2016 highlighted the potential role of microRNAs, and cyclin-dependent kinase inhibitors along with vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP9), and metallothionein isoform 3 (MT3) along with anti-apoptotic BCL2 in pituitary tumorigenesis including tumor invasiveness, recurrence, and metastasis [53]. While a comprehensive genomic landscape of pituitary carcinoma is yet to be defined, most alterations identified in pituitary carcinomas can also be identified in PitNETs. For this reason, at this time there are no diagnostic biomarkers or cytomorphological features that can accurately predict PitNET progression to metastatic behavior.

Effective medical therapies for pituitary carcinomas remain enigmatic. When standard dopamine and/or somatostatin analogs fail, targeted agents are frequently considered. Of these, the mTOR inhibitor everolimus [54] has been widely used in the management of pancreatic and other neuroendocrine neoplasms [55, 56]; in one case report of a metastatic pituitary carcinoma with an actionable STK11 mutation, the addition of everolimus with radiation therapy resulted in transient disease stabilization [57]. Bevacizumab has been used with some success in one published case [40]. Sunitinib represents another major targeted agent commonly used in neuroendocrine neoplasms [58,59,60]; however, we are unaware of any reports demonstrating successful use of this agent in managing refractory pituitary carcinomas.

Next in line following targeted agents are chemotherapeutic agents. Classical agents have been largely ineffective. More recently, case reports have advocated the use of the alkylating agent temozolomide as a potentially useful agent in managing pituitary carcinomas [28, 29, 36, 37, 40, 43, 61]. This was initially driven by the proven effectiveness of this agent in glioblastoma multiforme [28]. One study has suggested that the status of the mismatch repair protein MSH6 may impact response to treatment with temozolomide [62]. Subsequently, the addition of capecitabine, an oral pro-drug for 5-fluro-FU, to temozolomide has been noted to synergistically enhance apoptosis [63]. This is hypothesized to be the result of depletion of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) by capecitabine, thereby potentiating temozolomide action. These findings quickly led to the currently widely adopted use of the so-called CAPE/TEM combination in the management of neuroendocrine tumors [64]. To date, however, few reports [65, 66] have extended this combination protocol to pituitary tumors. It is, therefore, noteworthy that one of our patients in this series failed to show an objective response to this oral combination chemotherapeutic regimen.

Immunotherapy is a recent addition to the armamentarium of personalized oncology therapies. A single case of pituitary carcinoma has been reported to show significant reduction of metastatic tumor mass as well as reduced ACTH levels after nivolumab and ipilimumab therapies [41].

The use of PRRT has now emerged as another major therapeutic, non-surgical approach to the management of neuroendocrine neoplasms. Using somatostatin receptor agonists [67] or more recently receptor antagonists [68] as chaperones, these peptides deliver beta- and gamma-emitting radiation upon internalization. This dual property allows for effective delivery of cytotoxic internal radiation while permitting post-treatment imaging for internal dosimetry purposes. Experience thus far in the application of PRRT to PitNET management remains quite limited [69]. We predict, however, that this and other related radiopharmaceuticals will undoubtedly become the subject of intense investigations in refractory pituitary tumors including those meeting the diagnostic threshold of carcinomas.