Abstract Purpose Pituitary tumors are the second most common intracranial tumors, however, pituitary carcinoma is a rare clinical entity which represents only 0.1–0.2% of all pituitary tumors. Diagnosis of pituitary carcinoma requires the presence of metastasis. Early identification of pituitary carcinoma is difficult, and only recently have guidelines been published for the treatment of aggressive pituitary tumors. We present two cases from our institution, with a review of other cases available in literature in order to better characterize this rare disease. Methods A retrospective review of two patients with pituitary carcinoma treated at a tertiary medical center was performed. The MEDLINE database was searched for all cases of pituitary carcinoma. Information for age at diagnosis, sex, pituitary tumor type, latency period from pituitary tumor to presentation of carcinoma, sites of metastasis, number of surgical therapies, radiation and chemotherapy, and survival after diagnosis were collected. Results A total of 69 studies were available for review for a total of 72 unique cases. The average age at diagnosis was 46.3 years. The most common tumors were ACTH-secreting (34.7%), Prolactin-secreting (23.6%), and Null Cell (15.3%). The average latency period from pituitary tumor diagnosis to metastasis was 9 years. All patients underwent surgical therapy during their treatment, with an average of 2.76 procedures. The mortality rate was 54.8% with average time to death after diagnosis of approximately 10 months. Conclusions Pituitary carcinoma is a rare disease with high mortality rate and is a diagnostic and treatment challenge. Further study is required but is difficult due to its low incidence. Keywords Pituitary neoplasms · Pituitary carcinoma · Pituitary tumors · Endoscopic skull base surgery · Endoscopic pituitary surgery
Introduction Pituitary carcinoma (PC) is a rare clinical entity which comprises an estimated 0.1–0.2% of all pituitary tumors [1–6]. In 2004, the World Health Organization (WHO) defined pituitary tumors as typical, atypical, and carcinoma, and the distinguishing factors between typical and atypical pituitary * Frederick Yoo [email protected] 1
Department of Head and Neck Surgery, UCLA David Geffen School of Medicine, 10833 Le Conte Ave. 62‑132 CHS, Los Angeles, CA 90095‑1624, USA
Department of Neurosurgery, UCLA David Geffen School of Medicine, Los Angeles, USA
Department of Medicine, Division of Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, USA
adenoma are based upon histopathological analysis of number of mitoses, Ki-67 labeling index > 3%, and p53 immunohistochemical staining, whereas PC is diagnosed only in the presence of metastasis . Recent changes to the WHO definitions in 2017 have abandoned grading tumors as “atypical” due to its limited prognostic value [5, 6]. The changes do recommend evaluation of tumors based on proliferation markers (Ki-67 labeling index and mitotic count) and tumor invasiveness, though specific cutoffs are not provided . The definition of PCs remained unchanged, and due to its rarity, PCs present a diagnostic and management challenge. Many of these tumors require multiple surgical procedures and multimodal treatment strategies which are often only partially effective or not effective at all . Much of what is known about PC is anecdotal and comes from case reports and case series. A literature review performed in 2004 showed 140 reports in the English literature
at that time . This and other review articles cite a high mortality rate despite aggressive medical therapy, with one case series of 15 patients reporting a 66% mortality rate at 1 year, and 80% within 8 years after diagnosis of PC [7, 8]. Additionally, a Surveillance, Epidemiology, and End Results (SEER) database analysis was performed with a total of 9 patients which showed overall survival rates of 57.1 and 28.6% at 1 and 10 years, respectively . Recently, the European Society of Endocrinology (ESE) published clinical practice guidelines for the management of aggressive pituitary tumors . This study presents two additional cases of PC with cervical metastasis and reviews the literature of all cases of PC to examine the clinical characteristics, natural history, management, and outcomes of this disease.
Methods A retrospective chart review was conducted of two patients diagnosed with PC at a single tertiary academic medical center. These cases represent two cases of PC with cervical metastasis treated at our institution from over 700 pituitary tumor cases since 2007. A comprehensive search of MEDLINE was performed for all cases of PC. The search was performed with the query of “pituitary carcinoma” and all abstracts were reviewed. The search query yielded 103 studies presenting case reports/ series of PC in the English language from 1947 to the present. From these abstracts, 123 cases were identified. Sixtynine of these abstracts had full articles available for review. These articles were reviewed for a total of 72 cases, and patient information, including age at diagnosis, sex, histological type, time elapsed from diagnosis of pituitary tumor to malignant transformation, sites of metastasis, number of surgical procedures, treatment with radiation and chemotherapy, and survival after diagnosis of PC were collected.
Case 1 A 43-year-old male presented with a 10-year history of typeII diabetes mellitus and 1 week of blurry vision and right eyelid droop. He underwent magnetic resonance imaging (MRI) of the brain, which revealed a solid, heterogeneouslyenhancing pituitary tumor measuring 4.5 × 3.5 × 3.2 cm in size with suprasellar extension. He was initially thought to have a chordoma but upon further questioning, he reported a 30-lb weight gain in the past year with excessive bruising following minimal trauma, as well as a vertebral fracture from a small fender-bender. Additionally, he reported decreased libido and erectile dysfunction. Physical exam noted ophthalmoplegia of his right eye with ptosis, abdominal striae, and moon facies. Laboratory studies revealed a highly elevated ACTH and 24-h urinary free cortisol, with
reduced TSH, prolactin, and testosterone levels. A presumed diagnosis of Cushing’s disease was made. After consideration of treatment options, he underwent transnasal, transsphenoidal (TNTS) endoscopic pituitary surgery. Improvement in visual symptoms was noted postoperatively. Pathology revealed Crooke cell adenoma with dural and bony invasion. Immunohistochemical analysis revealed strong ACTH positivity, p53 positive nuclei, and a Ki-67 labeling index of 5–10%. After surgery, he had persistently elevated ACTH and 24-hour urinary free cortisol levels. On follow up, a postoperative MRI showed residual tumor in the pituitary bed though intraoperatively all visible tumor was resected. He underwent postoperative radiation therapy but continued to have persistently elevated ACTH and cortisol levels following completion of radiation therapy. He was trialed on multiple suppressive medications, including somatostatin analogs and D2 agonists, with limited success, and eventually medically controlled for 4 years with ketoconazole. Four years after his initial pituitary surgery, his ACTH and cortisol levels increased, and an MRI of the brain was obtained to evaluate for any interval changes in his sellar region revealing a stable appearance of the known sellar mass, with a new 1.6 × 2.6 cm left level III necrotic cervical lymph node, suspicious for metastatic disease (Fig. 1a). Further imaging with positron emission tomography (PET)/ computed tomography (CT) did not reveal a fluorodeoxyglucose (FDG)-avid lesion in the neck or any other site. A fine-needle aspiration (FNA) biopsy of the neck mass was consistent with metastatic neuroendocrine tumor, with positive synaptophysin and ACTH immunoreactivity, thus, he was diagnosed with PC. Subsequently, Ga-DOTATATE scintigraphy imaging was performed revealing evidence of residual tumor in the sellar region with uptake in the cervical region only. After discussion of his options, he underwent a left neck dissection 2 weeks later, with pathology demonstrating 9 of 27 lymph nodes positive for metastatic pituitary corticotroph carcinoma. After surgery, he had persistently elevated ACTH and cortisol levels. With minimal response to medical therapy and he underwent bilateral adrenalectomy 6 weeks later. He was managed medically with full exogenous steroid replacement. He was considered for possible postoperative neck radiation therapy but this was not pursued due to residual sellar tumor. On follow up MRI 6 months after his bilateral adrenalectomy, the patient was noted to have a new large globular sphenoid mass. It was unclear whether this was continued rapid growth of the tumor or possibly due to Nelson’s syndrome. He underwent revision TNTS surgery to remove the mass from the sphenoid and pituitary bed without complications and pathology returned as Crooke cell adenoma with strongly positive ACTH, Ki-67 of 10–15% with focal
Fig. 1 a Patient 1: Axial image of CT neck with contrast. Cervical metastatic lymph nodes inidcated by yellow arrows. b Patient 2: Axial image of MRI neck with contrast, T1 sequence post-contrast with fat saturation. Cervical metastatic lymph nodes indicated by yellow arrows
areas of 15–20%, and p53 negative immunohistochemistry. He was treated with Temozolomide (TMZ) for six cycles (5 days courses), with the first cycle dosed at 150 mg/m2/ day, and subsequent cycles of 200 mg/m2/day. After the TMZ therapy, he received proton therapy for a 35-day treatment period. Following these treatments, imaging studies revealed stabilization of his disease and reduction of ACTH levels, until 6 months post treatment PET scan revealed liver lesions. Biopsy of liver lesions revealed metastatic neuroendocrine tumor. He is now under consideration for immunotherapy trials.
Case 2 A 67-year-old female presented 8 years prior with severe headaches and was found to have a solid, enhancing pituitary macroadenoma measuring 2.3 × 2.0 × 2.3 cm in size on MRI. She was also noted to have elevated ACTH levels but normal 24-h urinary cortisol levels. She underwent initial treatment of her pituitary tumor with a TNTS approach, with near gross total resection, followed by radiosurgery. Pathology revealed positivity for ACTH, a Ki-67 labeling index up to 15%, and p53 staining at 10–15%. ACTH levels remained persistently elevated postoperatively. She had recurrence of her pituitary tumor 4 years later with extension into the clivus and the sphenoid sinus. She underwent a second TNTS procedure, with the tumor specimen once again positive for ACTH and an increased Ki-67 labeling index of 20%. The tumor recurred again 2 years
later and she underwent a third TNTS procedure, this time with gross total resection. This surgical specimen again showed positivity for ACTH and a Ki-67 labeling index of 20–25%, with scattered p53 positivity. She was followed postoperatively by her endocrinologist and treated with exogenous glucocorticoid and thyroid replacement therapy as she became hypocortisolemic following this surgery, though she was noted to have continued elevated ACTH levels. Two years after her third surgery, a surveillance MRI was performed and showed recurrence of her pituitary tumor centered around the right petrous apex and Meckel’s cave. She was referred for possible further surgical management of her pituitary region when two separate left neck masses were noted on examination (Fig. 1b). FNA biopsy was performed and showed metastatic PC, with immunoreactivity for ACTH and synaptophysin. A PET/CT scan was performed which showed FDG avidity of lymph nodes in levels IIB and V of the left neck. After discussion at a multidisciplinary tumor board, she was noted to be a high-risk surgical candidate due to encasement of the internal carotid arteries and history of perioperative venous thromboembolism with her previous surgeries. She was not a candidate for neck dissection due to residual tumor in the sella. She underwent TMZ therapy with a dose of 150 mg/m2/day for 5 days, for 10 cycles. Following TMZ therapy, she underwent radiation therapy of the neck and skull base due to progressive disease. She was also started on novolimumab, an anti-Programmed death-Ligand 1 (PD-L1) immunotherapy.
A total of 69 articles were reviewed, for 72 unique cases of PC presented in the literature. An additional 31 articles were excluded from this study due to inaccessibility of the full article for review. The patient characteristics of the cases reported and accessible are presented in Table 1. Among the cases, 40 were men and 32 women. The average age at diagnosis was 46.3 years, ranging from 9 to 75 years. The time period from diagnosis of pituitary tumor to identification of metastasis averaged 9.04 years (range of 0–31 years). Three patients were diagnosed with PC at time of postmortem autopsy when metastasis was discovered. The tumor histologic subtypes for the cases are summarized in Table 2. Five patients had tumors that secreted two hormones. The tumor type was not reported in one of the cases reviewed. Corticotrophinomas were most common with 25 cases (34.7%), followed by prolactinomas at 17 cases (23.6%), and null cell PC at 11 cases (15.3%). Fifteen of the cases had multiple metastatic sites. Most commonly, the site of metastasis was intracranial or spinal, comprising of 31 (43.1%) and 27 cases (37.5%), respectively. This was followed by liver metastasis with 10 cases (13.9%), and cervical lymph node and bone metastasis at 8 (11.1%) and 7 (9.7%), cases respectively. Central nervous system metastasis was found in 42 of our cases reviewed (58.3%), systemic metastasis in 23 cases (31.9%), and both CNS and systemic metastasis identified in 6 cases (8.3%). Treatment of the PC required multiple surgical procedures, as evidenced from the average of 2.76 surgeries for the cases reviewed, with one case receiving eight surgical procedures throughout the course of treatment. Radiation therapy was employed in the treatment of 61 of the cases reviewed (84.7%) and chemotherapy was given to 24 patients (33.3%). Sixteen of the patients treated with chemotherapy were treated with TMZ. Of the 72 cases, 34 deaths were reported in their case reports, 28 patients were alive at the time of publication, and 10 cases did not report the status of the patient. Survival at the time of publication ranged from 10 months to 21 years after diagnosis of PC. Of the patients whose deaths were reported, the average time to death after diagnosis of PC was 10 months. Of the deaths reported, 23 occurred within 1 year and all occurred within 3 years of diagnosis. Survival of patients receiving TMZ were also examined (Table 3). There was a small increase in 2-year survival in those receiving TMZ, however, chi-squared tests showed no statistically significant difference in 2-year survival of patients receiving TMZ compared to those who did not receive TMZ treatment in this series of patients.
Pituitary tumors are relatively common, representing approximately 10–15% of all intracranial tumors; on the other hand, PC is an exceedingly rare . In this case series, we present two cases of corticotrophic PC, one clinically apparent with signs and symptoms of Cushing’s disease and the other clinically silent at presentation. We also reviewed the case reports/series in literature to elucidate the clinical history, treatments, and outcomes in patients with PC. To date, there have been no large-scale clinical trials or retrospective analyses of large patient samples due to the low incidence of this disease. In fact, a SEER study was found in literature search and reviewed just nine cases of PC . The largest case series presented in the literature included just 24 cases . The natural history of PC is one of progression over time from a pituitary adenoma. One study proposed splitting cases into two groups: the majority of patients exhibit a variable clinical course which is indistinguishable from atypical pituitary adenoma except these tumors recur repeatedly and metastasize over a relatively protracted period, while a second smaller group of patients exhibit rapidly malignant behavior with local invasion, multiple recurrences, and early metastasis . Our two patients likely fall in the former group, with development of PC 4 and 8 years respectively after initial pituitary adenoma diagnosis. The latency period between the diagnosis of pituitary tumor and identification of metastasis in the reviewed cases was 9 years. Only six patients were diagnosed with a metastatic lesion within 1 year of diagnosis of pituitary tumor, with the rest of the cases diagnosed at 2 years or greater after diagnosis of a pituitary tumor. The definition of PC requires the presence of metastasis for diagnosis, which can be problematic from an early diagnosis standpoint. Distinguishing aggressive adenomas which will develop into PCs has proved challenging because aggressive adenomas can show varying degrees of nuclear atypia, cellular pleomorphism, and local invasion . Furthermore, it is unclear what proportion of these aggressive adenomas will progress into PCs [6–8]. Molecular markers have been investigated as possible ways of identifying tumors with potential for metastasis. Ki-67 Labeling Index (Ki-67 LI) using the MIB-1 antibody has been discussed the most extensively, with one study showing an increased mean Ki-67 level of 11.9 ± 3.4% in PCs compared to 1.4 ± 0.15% in non-invasive adenomas [1, 2, 4]. However, there is considerable variation in the Ki-67 level, ranging from 0 to 21.9% in one study, making this an imperfect marker of malignant potential . P53 tumor suppressor is another protein that has been implicated in PCs in multiple case reports and studies; however, there
Sakamoto et al.  Atienza et al.  Tonner et al.  Stewart et al.  Petterson et al.  Yamashita et al.  Mixson et al.  Cusimano et al.  Beauchesne et al.  Dayan et al.  Lormeau et al.  Garrao et al.  Kemink et al.  Masuda et al.  McCutcheon et al.  Zahedi et al.  Le Roux et al.  Sironi et al.  Pichard et al.  Suzuki et al.  Landman et al.  Roncaroli et al.  Roncaroli et al.  Tysome et al.  Ayuk et al.  Yamashita et al.  Brown et al.  Lim et al.  Sivan et al.  Fadul et al.  Fadul et al.  Tena-Suck et al.  Koyama et al.  Choi et al.  Koh et al. 
Null Cell PRL ACTH GH PRL GH TSH Null cell FSH, LH GH ACTH ACTH ACTH ACTH FSH, LH ACTH GH ACTH, PRL FSH ACTH ACTH FSH FSH, LH ACTH PRL PRL TSH, PRL PRL ACTH LH PRL PRL Null cell PRL Null Cell
Tumor type 1 week 4 years 3 years Post Mortem Post Mortem 16 years 5 years 11 years 2 years 6 years 10 years 14 years Post Mortem 2 years 2 years 2 years 2 years 9 years 15 years 6 years 14 years 2 years 20 years 16 years 5 years 10 months 7 years 4 years 9 years 8 years 2 years 12 years 15 years 6 months 7 years
Total # of surg. No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes No No Yes Yes Yes Yes No Yes
RT No No No No Yes No Yes No Yes No No No No No Yes No No No No No No No Yes No No No No Yes No Yes Yes No No No No
4 12 9 N/A N/A 2 NR Alive at time of publ. 24 Alive at time of publ. Alive at time of publ. 6 N/A 3 13 Alive at time of publ. Alive at time of publ. 17 10 Alive at time of publ. Alive at time of publ. 2 Alive at time of publ. Alive at time of publ. Alive at time of publ. 0.5 Alive at time of publ. Alive at time of publ. 18 Alive at time of publ. Alive at time of publ. 12 Alive at time of publ. 3 14
Scheithauer et al.  Figueiredo et al.  Guzel et al.  Pinchot et al.  Hagen et al.  Ilkhchoui et al.  Bode et al.  Yakoushina et al.  Curto et al.  Murakami et al.  Dudziak et al.  Moshkin et al.  Annamalai et al.  Lee et al.  Shastri et al.  Arnold et al.  Zhou et al.  Sreenan et al.  Morokuma et al.  Kovacs et al.  Zemmoura et al.  Phillips et al.  Miller et al.  Balili et al.  Lall et al.  Park et al.  Maclean et al.  Cornell et al.  Lee et al.  Lin et al.  Mendola et al.  Novruzov et al.  Takeuchi et al.  Borba et al.  Wang et al. 
Age M M F F F M F F M F M M M M F F M M M F M M F M M M M M M M M M M F M
Sex TSH NR Null Cell ACTH PRL GH ACTH Null Cell ACTH PRL Null cell ACTH ACTH TSH ACTH ACTH Null cell GH Null Cell ACTH PRL PRL ACTH PRL GH PRL Null Cell ACTH Null cell PRL ACTH GH ACTH ACTH ACTH
Tumor type 9 years 23 years 0 years 2.25 years 8.5 years 4 years 6 years 2.5 years 4 years 7 years 9 months 18 years 2 years 3 years 10 years 8 years 31 years 27 years 5 years 13 years 13 years 2 years 12 years 26 years 14 years 7 years 20 years 14 years 6 months 25 years 6 years 20 years 11 years 4 years 16 years
Total # of surg. Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No
RT No No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes No Yes No No Yes No Yes Yes No No No No No Yes Yes No Yes No No No No
Alive at time of publ. Alive at time of publ. 2 0.75 Alive at time of publ. NR Alive at time of publ. NR NR 3 5 Alive at time of publ. NR 6 11 Alive at time of publ. NR 36 NR 12 36 7 24 NR NR Alive at time of publ. NR 7 6 Alive at time of publ. 6 NR Alive at time of publ. 1 Alive at time of publ.
Alive at time of publ. Alive at time of publ. No No Yes Yes ID identification, RT radiation therapy, NR not reported, N/A not applicable (due to post-mortem identification of metastasis)
3 2 Spinal Cervical nodes 6 years 12 years GH GH F F 71 72 Wang et al.  Greenman et al. 
Case # Study
Table 1 (continued)
Time to ID of mets
Site of metastasis
Total # of surg.
have been reports of cases without p53 immunopositivity [1, 4, 8]. Additionally, one review stated that there is no evidence for the utility of P53 immunostaining on a regular basis . The 2017 WHO classification of pituitary tumors does not recommend clear cutoffs for Ki-67 index, P53 immunodetection, mitotic count or tumor invasion, but these markers are still recommended in the ESE clinical practice guidelines to be used in evaluation of tumors in clinical context with the caveat that no marker alone is sufficient to predict tumor behavior [5, 10]. The most common clinical presentation associated with development of PC is early recurrence after initial pituitary surgery, followed by multiple repeated surgeries for recurrence and extension, and this was evident in our review as these patients underwent an average 2.77 surgical interventions . The 2017 updated WHO classification of pituitary tumors does emphasize recognition of adenomas which are “special variants” known for more aggressive behavior with higher probability of recurrence regardless of histological grading, which include sparsely granulated somatotroph adenoma, plurihormonal PIT-1-positive adenoma, silent corticotroph adenoma, lactotroph adenomas in men and Crooke cell adenoma [5, 6]. The most common types of pituitary tumors that progress to carcinoma are corticotrophinomas and prolactinomas. Both cases presented from our institution were corticotrophs, one with Crooke cell adenoma and the other with a silent corticotroph adenoma, both of which are included in the “special variants” group. Crooke cell adenomas are aggressive corticotrophic pituitary tumors: they are nearly always invasive, prone to recurrence, and may progress to PCs more often [1, 2]. One case series of 31 patients with Crooke cell adenoma showed 60% of cases with recurrence, 24% with multiple recurrences, and two patients progressing to PC . Additionally, Nelson syndrome can lead to increased pituitary tumor growth, occurring after removal of cortisol-mediated negative feedback following bilateral adrenalectomy, and progression to metastasis [2, 3]. Silent corticotrophs also tend to exhibit aggressive clinical features, with greater propensity for macroadenoma size, local invasion (cavernous sinus, sphenoid sinus and bone), apoplexy and recurrence [1, 2, 83–86]. Additionally, the advent of transcription factor T-PIT immunostains has allowed for identification of hormone-immunonegative adenomas which show differentiation toward the corticotroph lineage which may help to identify more aggressive tumors which may act similarly to silent corticotroph adenomas . Thus, skull base surgeons and endocrinologists should be suspicious and closely surveil patients with aggressive histological features, aggressive tumor subtypes, and repeated recurrences. The diagnosis of PC is often preceded by the presence of unusual symptoms such as hearing loss, ataxia, motor impairment or neck mass, which prompts further diagnostic
Pituitary Table 2 Clinicopathologic characteristics of pituitary carcinoma patient cases
Gender Male Female Average age at diagnosis Tumor type ACTH Prolactin GH TSH FSH LH Null cell Sites of metastasis Intra-cranial Spinal Cervical lymph nodes Liver Bone Lung Endolymphatic sac Orbit Average time to Pituitary Carcinoma diagnosis after pituitary tumor diagnosis Average number of surgeries Radiation therapy Yes No Chemotherapy Yes Temozolamide treated No Mortality Alive at time of publication Death Average time to death after diagnosis of pituitary carcinoma Not reported
Table 3 Comparison of survival between treated with TMZ versus those treated without TMZ. Patients without reported survival status or adequate follow up were excluded from analysis
Alive at 2 years Deceased at 2 years
TMZ (n = 11)
No TMZ (n = 34)
5 (45.5%) 6 (54.5%)
11 (32.4%) 23 (67.6%) P = 0.43
testing . Metastases rarely dominate the clinical picture in early stages of disease and, at times, cases are only discovered postmortem [3, 14, 15, 23]. Two previous reviews have noted that systemic metastases appear more common than CNS metastases, but this review has shown more CNS
metastases noted in the cases reviewed than systemic metastases [1, 3]. Radiologic studies such as MRI and CT scans are most often utilized to identify metastases after the presentation of unusual symptoms. PET studies have aided identification of metastases in several cases, including case 2, but was unable to identify metastasis in case 1 . Radiotracers targeting somatostatin receptors have been used recently for detection of pituitary carcinomas with 111In-Labeled octreotide and 68Ga-DOTANOC used in scintigraphy, especially in ACTH-secreting carcinomas, as noted in Case 1 [3, 87, 88]. The treatment of PC is most often multimodal. Surgery and radiotherapy are options for locoregional treatment. Surgical therapy is rarely curative, but it has been mainstay of treatment. Gross total or subtotal resection of the sellar component is employed, often in multiple attempts, in the
course of managing PC to alleviate acute mass effects, along with other procedures to address metastases if amenable to resection [1, 4]. The ESE guidelines recommend surgery to be performed by an experienced pituitary surgeon, with consultation for repeat surgery prior to consideration of other treatment options . Surgical management with debulking appears to be the standard for treating the sellar component, as en bloc resection is usually not possible. Locoregional therapeutic surgical approaches to metastatic sites should be considered on a case-by-case basis [10, 87]. Radiation therapy is commonly employed for the primary management of pituitary adenomas, with control rates of 80–90% in nonfunctioning adenomas and 67–89% in hormonally active tumors, and with progression free rates of 92, 89 and 79% at 5, 10 and 15 years respectively . Adjuvant radiation therapy is recommended by the ESE guidelines for invasive tumors with pathologic markers indicating aggressive behavior with consultation of an experienced radiation oncologist in order to avoid damage to critical structures . Radiation therapy in the treatment of PC can be delivered as stereotactic radiosurgery or in fractionated radiation therapy over 5–6 weeks course . Success rates of these treatments have been varied and is difficult to assess due to variation in technique and doses administered in reported cases . Medical therapy is usually divided into two areas: biochemical control of the tumor and antiproliferative and/or pro-apoptotic therapy with chemotherapeutic agents . For biochemical control of aggressive pituitary tumors, guidelines recommend the use of dopamine agonists and somatostatin analogues depending on tumor type, likely with limited success though they may temporarily reduce tumor burden and improve symptoms [4, 10, 50]. Standard chemotherapeutic regimens employed for adenocarcinomas or sarcomas in the treatment of PC have shown poor response . Various chemotherapies have been utilized in PC including cyclo-hexyl-chloroethyl-nitrosurea (CCNU) in combination with 5-fluorouracil (5-FU) [1, 88]. TMZ has shown success in case reports and series and TMZ monotherapy is recommended as the first-line chemotherapy for aggressive pituitary adenomas and carcinomas with a reported volume reduction in 47% of patients [10, 39, 48, 52, 80, 81, 89–97]. TMZ was initially approved for use in refractory glioblastoma multiforme, and alkylates guanine at the O6 position causing DNA strand breaks and eventual cell death . It has been used off-label for PC since 2006 when first case reports were published detailing successful treatment with this agent. Several cohort studies of aggressive pituitary adenomas and carcinomas with populations ranging from 3 to 43 patients have shown partial or complete response in 71 of 149 patients in aggregate [48, 81, 89–98]. Our analysis showed no statistically significant difference in 2-year survival for those treated with TMZ versus those who were not treated with TMZ within this series of cases,
though there was a small non-significant benefit in survival with TMZ. However, this may be biased due to small sample size, and the fact that many of the patients receiving TMZ in these case reports started therapy late in their disease history as a final treatment attempt. A large study of 43 patients with aggressive pituitary tumors or pituitary carcinomas revealed a 51.2% response rate with a statistically significant improved overall survival in responders with a 44 months median survival, compared to 16 months among non-responders . Survival rates reported for PC that have been most often cited in the past have shown a mortality rate of 66% in 1 year and 80% over 8 years from a series of 15 cases . Our review similarly has shown that of the 62 cases which reported survival, 34 had died, with an average time to death after diagnosis of pituitary carcinoma of approximately 10 months. It is worthwhile to note, of the cases which had reported survival at time of publication, there were four cases which showed survival greater than 5 years after diagnosis of pituitary carcinoma, with one exceptional case of 21 years after diagnosis [31, 41, 44, 59]. The major limitation of this review is the limited follow up and variation in reporting of cases which limits the strength of conclusions made from this analysis. This is a common challenge in attempting to study rare conditions. Additionally, of the 103 abstracts that were found regarding pituitary carcinoma, only 69 were available for review through the MEDLINE database. Previous review papers have reported up to 140 cases in literature, but our search method yielded only 123 cases total, including abstracts. It is possible that some cases were not available through MEDLINE or there was some variation in the search query which yielded differing results. However, our review does represent a comprehensive and in-depth look at the 72 cases presented.
Conclusion Pituitary carcinoma is a rare disease which presents a diagnostic and treatment challenge. Skull base surgeons should be aware of the potential for metastases from a pituitary carcinoma with locally aggressive pituitary tumors, even years after initial presentation. Our review confirmed previous reports of a high mortality associated with this diagnosis. Early identification of pituitary tumors at risk for progression to pituitary carcinoma is difficult, and no combination of histopathological or immunohistochemical analyses has conclusively been able to identify pituitary adenomas that will progress to carcinoma. Suspicion should be raised when patients present with tumors of aggressive subtypes and histological features, and with multiple recurrences. Surgical therapy, radiation, and chemotherapy have all been employed in case reports with varied success, with
combination therapy in a multidisciplinary setting necessary for these patients. TMZ has shown promise and is now recommended as first-line chemotherapy. Further study is required to determine the best treatment strategies for pituitary carcinoma, but due to its low incidence, it will be a challenging endeavor.
Compliance with ethical standards Conflict of interest There are no financial disclosures or conflict of interest for any authors.
References 1. Heaney AP (2011) Pituitary carcinoma: difficult diagnosis and treatment. J Clin Endocrinol Metab 96(12):3649–3660 2. Heaney A (2014) Management of aggressive pituitary adenomas and pituitary carcinomas. J Neurooncol 117:459–468 3. Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB (2005) Clinical review: diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab 90(5):3089–3099 4. Scheithauer BW, Kurtkaya-Yapicier O, Kovacs KT, Young WF Jr., Lloyd RV (2005) Pituitary carcinoma: a clinicopathological review. Neurosurgery 56:1066–1074 5. Lopes MBS (2017) The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol 134:521–535 6. Mete O, Lopes MB (2017) Overview of the 2017 WHO classification of pituitary tumors. Endocr Pathol 28:228–243 7. Ragel BT, Couldwell WT (2004) Pituitary carcinoma: a review of the literature. Neurosurg Focus 16(4):E7 8. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF, Lloyd RV, Davis DH, Guthrie BL, Schoene WC (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79(4):804–812 9. Hansen TM, Batra S, Lim M, Gallia GL, Burger PC, Salvatori R, Wand G, Quinones-Hinojosa A, Kleinberg L, Redmond KJ (2014) Invasive adenoma and pituitary carcinoma: a SEER database analysis. Neurosurg Rev 37, 279–286 10. Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM (2017) European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumors and carcinomas. Eur J Endocrinol 178(1):G1–24 11. Sakamoto T, Itoh Y, Fushimi S, Kowada M, Saito M (1990) Primary pituitary carcinoma with spinal cord metastasis—case report. Neurol Med Chir (Tokyo) 30(10):763–767 12. Atienza DM, Vigersky RJ, Lack EE, Carriaga M, Rusnock EJ, Tsou E, Cerrone F, Kattah JG, Sausville EA (1991) Prolactinproducing pituitary carcinoma with pulmonary metastasis. Cancer 68(7):1605–1610 13. Tonner D, Belding P, Moore SA, Schhlechte JA (1992) Intracranial dissemination of an ACTH secreting pituitary neoplasm— a case report and review of the literature. J Endocrinol Invest 15(5):387–391 14. Stewart PM, Carey MP, Graham CT, Wright AD, London DR (1992) Growth hormone secreting pituitary carcinoma: a case report and literature review. Clin Endocrinol (Oxf) 37(2):189–194 15. Petterson T, MacFarlane IA, MacKenzie JM, Shaw MD (1992) Prolactin secreting pituitary carcinoma. J Neurol Neurosurg Psych 55(12):1205–1206
16. Yamashita S, Izumi M, Nagataki S (1992) Acromegaly and pituitary carcinoma. Ann Intern Med 117(12):1057–1058 17. Mixson AJ, Friedman TC, Katz DA, Feuerstein IM, Taubenberger JK, Colandrea JA, Doppman JL, Oldfield EH, Weintraub BD (1993) Thyrotropin-secreting pituitary carcinoma. J Clin Endocrinol Metab 76(2):529–533 18. Cusimano MD, Ohori P, Martinez AJ, Jungreis C, Wright DC (1994) Pituitary carcinoma. Skull Base Surg 4(1):46–51 19. Beauchesne P, Trouillas J, Barral F, Brunon J (1995) Gonadotropic pituitary carcinoma: case report. Neurosurgery 37(4):810–815 20. Dayan C, Guilding T, Hearing S, Thomas P, Nelson R, Moss T, Bradshaw J, Levy A, Lightman S (1996) Biochemical cure of recurrent acromegaly by resection of cervical spinal canal metastasis. Clin Endocrinol (Oxf) 44(5):597–602 21. Lormeau B, Miossec P, Sibony M, Valensi P, Attali JR (1997) Adrenocorticotropin-producing pituitary carcinoma with liver metastasis. J Endocrinol Invest 20(4):230–236 22. Garrao AF, Sobrinho LG, Pedro-Oliviera, Bugalho MJ, Boavida JM, Raposo JF, Loureiro M, Limbert E, Costa I, Antunes JL (1997) ACTH-producing carcinoma of the pituitary with haematogenic metastasis. Eur J Endorcrinol 137(2):176–180 23. Kemink SA, Wesseling P, Pieters GF, Verhofstad AA, Hermus AR, Smals AG (1999) Progression of a Nelson’s adenoma to pituitary carcinoma: a case report and review of the literature. J Endocrinol Invest 22(1):70–75 24. Masuda T, Akasaka Y, Ishikawa Y, Ishii T, Isshiki I, Imafuku T, Ogihara T, Miyazaki H, Asuwa N (1999) An ACTH-producing pituitary carcinoma developing Cushing’s disease. Pathol Res Pract 195(3):183–187 25. McCutcheon IE, Pieper DR, Fuller GN, Benjamin RS, Friend KE, Gagel RF (2000) Pituitary carcinoma containing gonadotropins: treatment by radical excision and cytotoxic chemotherapy: case report. Neurosurgery 46(5):1233–1239 26. Zahedi A, Booth Gl, Smyth HS, Farrell WE, Clayton RN, Asa SL, Ezzat S (2001) Distinct clonal composition of primary and metastatic adrenocorticotrophic hormone-producing pituitary carcinoma. Clin Endocrinol (Oxf) 55(4):549–556 27. Le Roux CW, Mulla A, Meeran K (2001) Pituitary carcinoma as a cause of acromegaly. N Engl J Med 345(22):1645–1646 28. Sironi M, Cenacchi G, Cozzi L, Tonnarelli G, Iacobellis M, Trere D, Assi A (2002) Progression on metastatic neuroendocrine carcinoma from a recurrent prolactinoma: a case report. J Clin Pathol 55(2):148–151 29. Pichard C, Gerber S, Laloi M, Kujas M, Clemenceau S, Ponvert D, Bruckert E, Turpin G (2002) Pituitary carcinoma: report of an exceptional case and review of the literature. J Endorcrinol Invest 25(1):65–72 30. Suzuki K, Morii K, Nakamura J, Kaneko S, Ukisu J, Hanyu O, Nakagawa O, Aizawa Y (2002) Adrenocorticotropin-producing pituitary carcinoma with metastasis to the liver in a patient with Cushing’s disease. Endocr J 49(2):153–158 31. Landman RE, Horwith M, Peterson RE, Khandji AG, Wardlaw SL (2002) Long-term survival with ACTH-secreting carcinoma of the pituitary: a case report and review of the literature. J Clin Endocrinol Metab 87(7):3084–3089 32. Roncaroli F, Nose V, Scheithauer BW, Kovacs K, Horvath E, Young WF Jr., Lloyd RV, Bishop MC, Hsi B, Fletcher JA (2003) Gonadotropic pituitary carcinoma: HER-2/neu expression and gene amplification. Report of 2 cases. J Neurosurg 99(2):402–408 33. Tysome J, Gnanalingham KK, Chopra I, Mendoza N (2004) Intradural metastatic spinal cord compression from ACTH-secreting pituitary carcinoma. Acta Neurochir (Wien) 146(11):1251–1254 34. Ayuk J, Natarajan G, Geh JI, Mitchell RD, Gittoes NJ (2005) Pituitary carcinoma with a single metastasis causing cervical spinal cord compression. Case report. J Neurosurg Spine 2(3):349–353
Pituitary 35. Yamashita H, Nakagawa K, Tago M, Nakamura N, Shiraishi K, Yamauchi N, Ohtomo K (2005) Pathological changes after radiotherapy for primary pituitary carcinoma: a case report. J Neurooncol 75(2):209–214 36. Brown RL, Muzzafar T, Wollman R, Weiss RE (2006) A pituitary carcinoma secreting TSH and prolactin: a non-secretory adenoma gone awry. Eur J Endocrinol 154(5):639–643 37. Lim S, Shahinian H, Maya MM, Yong W, Heaney AP (2006) Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol 7(6):518–520 38. Sivan M, Nandi D, Cudlip S (2006) Intramedullary spinal metastasis (ISCM) from pituitary carcinoma. J Neurooncol 80(1):19–20 39. Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ, Simmons NE (2006) Long-term response of pituitary carcinoma to temozolomide. Report of two cases. J Neurosurg 105(4):621–626 40. Tena-Suck ML, Salinas-Lara C, Sanchez-Garcia A, RembaoBojorquez D, Ortiz-Plata A (2006) Late development of intraventricular papillary pituitary carcinoma after irradiation of prolactinoma. Surg Neurol 66(5):527–533 41. Koyama J, Ikeda K, Shose Y, Kimura M, Obora Y, Kohmura E (2007) Long-term survival with non-functioning pituitary carcinoma—case report. Neurol Med Chir (Tokyo) 47(10):475–478 42. Choi G, Choi HJ, Kim YM, Choi SH, Cho YC, Kim Y, Suh JH, Cha HJ (2007) Pituitary carcinoma with mandibular metastasis: a case report. J Korean Med Sci 22(Suppl):145–148 43. Koh KP, Lee HY, Rajasoorya RC (2008) Triple jeopardy in the pituitary. Pituitary 11(3):331–336 44. Scheithauer BW, Kovacs K, Nose V, Lombardero M, Osamura YR, Lloyd RV, Horvath E, Pagenstecher A, Bohl JE, Tews DS (2009) Multiple endocrine neoplasia type 1-associated thyrotropin producing pituitary carcinoma: report of a probable de novo example. Hum Pathol 40(2):270–278 45. Figueiredo EG, Palva WS, Teixeira MJ (2009) Extremely late development of pituitary carcinoma after surgery and radiotherapy. J Neurooncol 92(2):219–222 46. Guzel A, Tatti M, Senturk S, Guzel E, Cayli SR, Sav A (2008) Pituitary carcinoma presenting with multiple metastases: case report. J Child Neurol 23(12):1467–1471 47. Pinchot SN, Sipple R, Chen H (2008) ACTH-producing carcinoma of the pituitary with refractory Cushing’s Disease and hepatic metastases: a case report and review of literature. World J Surg Oncol 7:39 48. Hagen C, Schroeder HD, Hansen S, Hagen C, Andersen M (2009) Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. Eur J Endocrinol 161(4):631–637 49. Ilkhchoui Y, Appelbaum DE, Pu Y (2010) FDG-PET/CT findings of a metastatic pituitary tumor. Cancer Imaging 10:114–116 50. Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP, Thome C (2010) SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes 118(10):760–763 51. Yakoushina TV, Lavi E, Hoda RS (2010) Pituitary carcinoma diagnosed on fine needle aspiration: report of a case and review of pathogenesis. Cytojournal 7:14 52. Curto L, Torre ML, Ferrau F, Pitini V, Altavilla G, Granata F, Longo M, Hofland LJ, Trimarchi F, Cannavo S (2010) Temozolomide-induced shrinkage of a pituitary carcinoma causing Cushing’s disease-report of a case and literature review. Sci World J 10:2132–2138 53. Murakami M, Mizutani A, Asano S, Katakami H, Ozawa Y, Yamazaki K, Ishida Y, Takano K, Okinaga H, Matsuno A (2011) A mechanism of acquiring temozolomide
57. 58. 59. 60. 61. 62.
resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma: case report. Neurosurgery 68(6):E1761–E1767 Dudziak K, Honegger J, Bornemann A, Horger M, Mussig K (2011) Pituitary carcinoma with malignant growth from first presentation and fulminant clinical course-case report and review of the literature. J Clin Endocrinol Metab 96(9):2665–2669 Moshkin O, Syro LV, Scheithauer BW, Ortiz LD, Fadul CE, Uribe H, Gonzalez R, Cusimano M, Horvath E, Rotondo F, Kovacs K (2011) Aggressive silent corticotroph adenoma progressing to pituitary carcinoma: the role of temozolomide therapy. Hormomes (Athens) 10(2):162–167 Annamalai AK, Dean AF, Kandasamy N, Kovacs K, Burton H, Halsall DJ, Shaw AS, Antoun NM, Cheow HK, Kirollos RW, Pickard JD, Simpson HL, Jefferies SJ, Burnet NG, Gurnell M (2012) Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature. Pituitary 15(3):276–287 Lee W, Cheung AS, Freilich R (2012) TSH secreting pituitary carcinoma with intrathecal drop metastases. Clin Endocrinol (Oxf) 76(4):604–606 Shastri BR, Nanda A, Fowler M, Levine SN (2013) Adrenocorticotropic hormone-producing pituitary carcinoma with intracranial metastasis. World Neurosurg 79(2):404 Arnold PM, Ratnasingam D, O’Neil MF, Johnson PL (2012) Pituitary carcinoma recurrent to the lumbar intradural extramedullary space: case report. J Spinal Cord Med 35(2):118–121 Zhou Q, Chang H, Gao Y, Cui L (2013) Tumor-to-tumor metastasis from pituitary carcinoma to radiation-induced meningioma. Neuropathology 33(2):209–212 Sreenan S, Sengupta E, Tormey W, Landau R (2012) Metastatic pituitary carcinoma in a patient with acromegaly: a case report. J Med Case Rep 6:322 Morokuma H, Ando T, Hayashida T, Horie I, Inoshita N, Murata F, Ueki I, Nakamura K, Imaizumi M, Usa T, Kawakami A (2012) A case of nonfunctioning pituitary carcinoma that responded to temozolomide treatment. Case Rep Endocrinol. https://doi. org/10.1155/2012/645914 Kovacs GL, Goth M, Rotondo F, Scheithauer BW, Carlsen E, Saadia A, Hubina E, Kovacs L, Szabolcs I, Nagy P, Czirjak S, Hanzely Z, Kovacs K, Horvath E, Korbonits M (2013) ACTHsecreting Crooke cell carcinoma of the pituitary. Eur J Clin Invest 43(1):20–26 Zemmoura I, Wierinckx A, Vasiljevic A, Jan M, Trouillas J, Francois P (2013) Aggressive and malignant prolactin pituitary tumors: pathological diagnosis and patient management. Pituitary 16(4):515–522 Phillips J, East HE, French SE, Melcescu E, Hamilton RD, Nicholas WC, Kratkin JF, Parent AD, Luzardo G, Koch CA (2012) What causes a prolactinoma to be aggressive or to become a pituitary carcinoma?. Hormones (Athens) 11(4):477–482 Miller BA, Tanaka T, Ioachimescu AG, Vincentelli C, Appin CL, Oyesiku NM (2013) Transformation of a silent adrenocorticotrophic pituitary tumor into central nervous system melanoma. J Investig Med High Impact Case Rep. https://doi. org/10.1177/2324709613494008 Balili I, Sullivan S, Mckeever P, Barkan A (2014) Pituitary carcinoma with endolymphatic sac metastasis. Pituitary 17(3):210–213 Lall RR, Shafizadeh SF, Lee KH, Mao Q, Mehta M, Raizer J, Bendok BR, Chandler JP (2013) Orbital metastasis of pituitary growth hormone secreting carcinoma causing lateral gaze palsy. Surg Neurol Int 4:59 Park KS, Hwang JH, Hwang SK, Kim S, Park SH (2014) Pituitary carcinoma with fourth ventricle metastasis: treatment by excision and Gamma-knife radiosurgery. Pituitary 17(6):514–518
Pituitary 70. Maclean J, Aldridge M, Bomanji J, Short S, Fersht N (2014) Peptide receptor radionuclide therapy for aggressive atypical pituitary adenoma/carcinoma: variable clinical response in preliminary evaluation. Pituitary 17(6):530–538 71. Cornell RF, Kelly DF, Bordo G, Carroll TB, Duong HT, Kim J, Takasumi Y, Thomas JP, Wong YL, Findling JW (2013) Chemotherapy induced regression of an adrenocorticotropin-secreting pituitary carcinoma accompanied by secondary adrenal insufficiency. Case Rep Endocrinol. https://doi.org/10.1155/2013/675298 72. Lee HH, Hung SH, Tseng TM, Lin YH, Cheng JC (2014) Undifferentiated carcinoma of the pituitary gland: a case report and review of the literature. Oncol Lett 7(3):778–780 73. Lin GC, Adams ME, Arts HA (2014) Lesions of the petrous ridge: metastatic pituitary carcinoma with discussion of differential diagnosis. Otol Neurotol 35(4):645–648 74. Mendola M, Passeri E, Ambrosi B, Corbetta S (2014) Multiple cerebral hemorrhagic foci from metastases during temozolomide treatment in a patient with corticotroph pituitary carcinoma. J Clin Endocrinol Metab 99(8):2623–2624 75. Novruzov F, Aliyev JA, Jaunmuktane Z, Bomanji JB, Kayani I (2015) The use of (68)Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177)Lu DOTATATE therapy in pituitary carcinoma. Clin Nucl Med 40(1):47–49 76. Takeuchi K, Hagiwara Y, Kanaya K, Wada K, Shiba M, Kato Y (2014) Drop metastasis of adrenocorticotropic hormone-producing pituitary carcinoma to the cauda equina. Asian Spine J 8(5):680–683 77. Borba CG, Batista RL, Musolino NR, Machado VC, Alcantara AE, da Silva GO, Cescato S, da Cunha VA, Neto MB (2015) Progression of an invasive ACTH pituitary macroadenoma with Cushing’s disease to pituitary carcinoma. Case Rep Oncol Med. https://doi. org/10.1155/2015/810367 78. Wang YQ, Fan T, Zhao XG, Liang C, Qi XL, Li JY (2015) Pituitary carcinoma with intraspinal metastasis: report of two cases and review of literature. Int J Clin Exp Pathol 8(8):9712–9717 79. Greenman Y, Woolf P, Coniglio J, O’Mara R, Pei L, Said JW, Melmed S (1996) Remission of acromegaly caused by pituitary carcinoma after surgical excision of growth hormone-secreting metastasis detected by 111-Indium pentetreotide scan. J Clin Endocrinol Metab 81(4):1628–1633 80. Liu JK, Patel J, Eloy JA (2015) The role of temozolomide in the treatment of aggressive pituitary tumors. J Clin Neurosci 22(6):923–929 81. Bengtsson D, Schroder HD, Andersen M, Maiter D, Berinder K, Feldt Rasmussen U, Rasmussen AK, Johannsson G, Hoybye C, van der Lely AJ, Petersson M, Ragnarsson O, Burman P (2015) Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolamide. J Clin Endocrinol Metab 100(4):1689–1698 82. George DH, Scheithauer BW, Kovacs K, Horvath E, Young WF Jr., Lloyd RV, Meyer FB (2003) Crooke’s cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma. Am J Surg Pathol 27(10):1330–1336 83. Cooper O (2015) Silent corticotroph adenomas. Pituitary 18:225–231 84. Jahangiri A, Wagner JR, Pekmezci M, Hiniker A, Chang EF, Kunwar S, Blevins L, Aghi MK (2013) A comprehensive long-term retrospective analysis of silent corticotrophic adenomas vs hormonenegative adenomas. Neurosurgery 73:8–17 85. Webb KM, Laurent JJ, Okonkwo DO, Lopes MB, Vance ML, Laws ER Jr. (2003) Clinical characteristics of silent corticotrophic adenomas and creation of an internet-accessible database to facilitate their multi-institutional study. Neurosurgery 53:1076–1084 86. Xu Z, Ellis S, Lee CC, Starke RM, Schlesinger D, Vance ML, Lopes MB, Sheehan J (2014) Silent corticotroph adenomas after stereotactic radiosurgery: a case-control study. Int J Radiat Oncol Biol Phys 90:903–910
87. Veit JA, Boehm B, Luster M, Scheuerle A, Rotter N, Rettinger G, Scheithauer M (2013) Detection of paranasal ectopic adrenocorticotropic hormone-secreting pituitary adenoma by Ga-68-DOTANOC positron-emission tomography-computed tomography. Laryngoscope 123:1132–1135 88. Lopes MB, Scheithauer BW, Schiff D (2005) Pituitary carcinoma: diagnosis and treatment. Endocrine 28(1):115–121 89. Campdera M, Palacios N, Aller J, Magallon R, Martin P, Saucedo G, Lilienfeld H, Estrada J (2016) Temozolomide for aggressive ACTH tumors: failure of a second course of treatment. Pituitary 19(2):158–166 90. Losa M, Bogazzi F, Cannavo S, Ceccato F, Curto L, De Marinis L, Iacovazzo D, Lombardi G, Mantovani G, Mazza E, Minniti G, Nizzoli M, Reni M, Scaroni C (2016) Temozolomide therapy in patients with aggressive pituitary adenomas and carcinomas. J Neurooncol 126(3):519–525 91. Bruno OD, Juarez-Allen L, Christiansen SB, Manavela M, Danilowicz K, Vigovich C, Gomez RM (2015) Temozolomide therapy for aggressive pituitary tumors: results in a small series of patients from Argentina. Int J Endocrinol. https://doi.org/10.1155/2015/587893 92. Whitelaw BC, Dworakowska D, Thomas NW, Barazi S, RiordanEva P, King AP, Hampton T, Landau DB, Lipscomb D, Buchanan CR, Gilbert JA, Aylwin SJ (2012) Temozolomide in the management of dopamine agonist-resistant prolactinomas. Clin Endocrinol (Oxf) 76(6):877–886 93. Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr., Vance ML, Thorner MO, Laws ER Jr., Lopes MB (2010) Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab 95(11):E280–E290 94. Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, Dufour H, Gaillard S, Francois P, Jouanneau E, Passagia JG, Bernier M, Cornelius A, Figarella-Branger D, Trouillas J, Borson-Chazot F, Brue T (2010) Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab 95(10):4592–4599 95. Losa M, Mazza E, Terreni MR, McCormack A, Gill AJ, Motta M, Cangi MG, Talarico A, Mortini P, Reni M (2010) Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases. Eur J Endocrinol 163(6):843–861 96. Ceccato F, Lombardi G, Manara R, Emanuelli E, Denaro L, Milanese L, Gardiman MP, Bertorelle R, Scanarini M, D’Avella D, Occhi G, Boscaro M, Zagonel V, Scaroni C (2015) Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center. J Neurooncol 122(1):189–196 97. Hirohata T, Asano K, Ogawa Y, Takano S, Amano K, Isozaki O, Iwai Y, Sakata K, Fukuhara N, Nishioka H, Yamada S, Fujio S, Arita K, Takano K, Tominaga A, Hizuka N, Ikeda H, Osamura RY, Tahara S, Ishii Y, Kawamata T, Shimatsu A, Teramoto A, Matsuno A (2013) 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 98(3):1130–1136 98. Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, Desailloud R, Jublanc C, Lebrun-Frenay C, Sadoul JL, Taillandier L, Batisse-Lignier M, Bonnet F, Bourciqaux N, Bresson D, Chabre O, Chanson P, Garcia C, Haissaguerre M, Reznik Y, Borot S, Villa C, Vasiljevic A, Gaillard S, Jouanneau E, Assie G, Raverot G (2017) Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur J Endocrinol 176(6):769–777