The concept of a dedicated PTCOE has an international requirement to identify centers that can optimally support patients harboring pituitary adenomas. Recent progress in neurosurgical procedures, novel medical therapies for hormonally-active pituitary adenomas [13], as well as improved diagnostic tools for hypopituitarism and its treatment paradigms [14], and the management of systemic complications caused by pituitary tumors [15, 16] have paved the way for individualized therapy and follow-up. This patient-centric approach is best provided by multidisciplinary teams of dedicated experts, who can implement and adapt to evolving guidelines, comprised of experts in surgical techniques and medical treatments along with supporting units and nursing facilities [9].
There is a risk that this urgent need could generate self-appointed reference centers around the world with a wide heterogeneity in the quality of care provided, which might create uncertainty and confusion among patients and health authorities in terms of recognition of those centers effectively granting the best care for these rare diseases. The basic criteria for defining a PTCOE were published by a panel appointed by the Pituitary Society in 2017 [9]. However, these theoretical criteria required validation in real-life practice before being accepted globally and used for PTCOE accreditation. We designed a voluntary study involving several high-volume tertiary pituitary care centers selected by a panel of experts appointed by the Pituitary Society to test qualitatively the fulfillment of previously formulated criteria for PTCOEs. When the review process provided positive qualitative evaluations, we analyzed large amount of data provided by each center to benchmark the activities and infer numerical thresholds against which a given pituitary center could be compared, before being accredited as “excellent”.
Our results suggest that to perform an adequate assessment of each center, the volume of information to be collected is quite substantial and this, together with the challenges of the pandemic, could lengthen the process of data collection within a center. This process requires dedicated personnel at the center to extract and synthesize the requested data from existing databases in different units, which may be administratively challenging in many cases. On the other hand, accrediting bodies will also rely on dedicated personnel to review the data, which will require a significant organizational effort to evaluate requests for accreditation as PTCOEs from around the world. A further organizational burden may be reflected by a need for on-site visits to verify reliability of submitted data, as performed for assessment of excellence in care for other diseases. Our study did not include a site visit, which would have been a challenge to perform in the setting of the COVID-19 pandemic [17]. In fact, an “on-site” visit could become a future component of the accreditation process.
The role of the endocrine component of the PTCOE consists of evaluating pituitary disease, establishing the diagnosis, determining the optional treatment plan together with neurosurgeons regarding surgical intervention, providing support for peri-operative care, and providing long-term follow-up management [18, 19]. The 2017 Pituitary Society panel paper defined qualitatively the criteria for excellence of the Endocrine Unit, but one of its main limitations was the lack of quantitative definitions of the criteria, due to the absence of reference data in the medical literature [9]. In this regard, our study provides the first systematic attempt, based on the large volume of data produced by surveying established reputable pituitary centers. Interestingly, we were able to define that a PTCOE should have at least four, ideally six, dedicated endocrinologists expert in pituitary diseases. In this regard, in any forthcoming accreditation process, some practical considerations should be taken into account, including the specific site environment, such as support staff and percentage effort in clinical care of each endocrinologist. In fact, with a progressive decline of in-hospital practicing endocrinologists worldwide, there is a risk that only a few centers could grant this type of effort, unless more resources are allocated and endocrine units dedicated solely or predominantly to pituitary disease are established. Moreover, the ability to have nurses dedicated to pituitary disease is already limited in the large centers surveyed and may not be possible in some countries. Based on our data, one such nurse could be acceptable for a PTCOE. With current global nursing shortages, many centers may not be able to have a dedicated nurse, so this criterion for PTCOE accreditation may require further consideration.
Regarding the volume of activity, a typical high-volume pituitary center can be defined as a center in which > 1000 pituitary patients per year are seen, with 850 being the minimal threshold. Diagnosis of pituitary disease is based on accuracy of measurement of biochemical parameters, so expert endocrinologists must have a thorough knowledge of laboratory procedures for hormone analysis [20]. Since dynamic tests are typically performed in the pituitary center environment, and endocrine patients are rarely hospitalized (except for surgeries or concomitant acute illnesses), the number of dynamic tests performed per year does appear to be the most favorable criterion to benchmark the volume of activity of the endocrine unit of a proposed PTCOE, which should be > 300 tests/year. This information may be even more important, since in the evaluation of an endocrine unit, it may allow us to assess experience with other pituitary diseases. In fact, most dynamic tests are performed for diagnosis of pituitary hormone deficiencies, which may be unrelated to pituitary tumors.
Endocrinologists play a life-long role in the management of patients before and after surgical interventions and determine optimal treatment to achieve remission or biochemical control of the pituitary disease [21–26]. The efficacy of medical treatment for secreting pituitary adenomas has been evaluated primarily in retrospective studies [27, 28]. Therefore, as reported in the 2017 statement [9], expertise in optimal use of all available medical tools for a given disease should be required. A reasonable criterion for quantifying this parameter is the rate of control achieved. Clearly, the same definition of biochemical control should be used by each center, consistent with recent guidelines [16, 15] to allow homogeneous assessment of centers internationally and to avoid variability observed in reporting remission in Cushing’s disease. Interestingly, the cumulative degree of biochemical control achieved in surveyed pituitary centers was quite homogeneous and similar, if not better than that reported [29].
As qualitatively outlined in the 2017 criteria [9], two characteristics relevant to effective medical management of pituitary tumors include:
1. A track record of relevant publications in peer-reviewed journals, which allows evaluation of center activities by peers and benchmarks clinical research activity expected from a PTCOE. In general, outcome studies led by the endocrinologists, also involved surgeons and radiation oncologists. Finally, while the assessment of publication quality goes beyond the scope of the accreditation process, specific guidelines for defining publication standards for PTCOEs could be established.
2. Participation of the Center in clinical trials involving new therapeutic molecules. This is an additional opportunity for patients not responders to standard therapies and allows the center to gain insights and experience for future treatment [30], once it becomes generally available. Our results suggest that surveyed centers are involved in a median of at least 4 clinical trials every year. Clearly, this number can be achieved in high-volume centers. However, it is interesting to note that one center in our survey was not involved in any trial.
Although recent advances in medical treatment of pituitary tumors have been stellar, undoubtedly a PTCOE is dependent on the presence of a dedicated and excellent neurosurgical group, devoted to pituitary surgery by endonasal TS or transcranial approaches. In fact, TS is recommended as the first-line therapy for most sellar tumors [31, 32]. The goals of pituitary surgery include rapid resolution of tumor mass effect, determining decompression of the optic apparatus and of the normal pituitary gland and stalk, as well as the elimination of hormonal hypersecretion. Surgical experience and caseload have a significant role in achieving optimal results in addition to tumor-related factors [31, 7]. Studies of acromegaly patients have confirmed the relationship between surgical volume and patient outcomes [33, 34]. In a review of 1215 cases of acromegaly treated at 22 centers in the UK, Bates et al. [35] confirmed that surgical outcome significantly improved in the last 4 years of the study after directing care to a small number of subspecialists. A similar observation was reported in Japan, with an increase in surgical success for acromegaly from 37 to 81% with transition to a single surgeon strategy [36]. Surgical expertise requires specific training at a high-quality center performing a large number of pituitary interventions each year after training in neurosurgery, and ongoing activity. Considering that most centers serve a fixed number of inhabitants, the solution proposed in the 2017 statement, as well as in subsequent papers, would be to concentrate pituitary neurosurgeons at a PTCOE that covers the TS needs of a region [9]. An ideal reference center for a region may be formed by 2 to 4 expert neurosurgeons performing TS operations, including macro- and microadenomas, serving a population of 2.5 to 5 million inhabitants, with a proportional increase in the work load [37, 9]. According to our validated results, 3 surgeons should ideally be devoted to pituitary surgery at a given center. The objective ideal population served by a neurosurgery unit in the present study is 3.7 million, but greater than 1.5 million is the minimum acceptable, consistent with a previous report [7]. Although the 2017 statement raised the issue that an organization based on a single pituitary surgeon might have drawbacks, objective results showed that a single surgeon can be considered as acceptable. The ideal number of pituitary nurses is 3, but it has to be noted that even some high volume centers do not have dedicated nurses. The only numerical criterion provided in the 2017 statement concerned the need for at least 50 pituitary procedures every year, data that were based on previous neurosurgical audits and appeared to be slightly higher than the 25 annual intervention rates previously proposed. Importantly, results from previous surveys suggest that most neurosurgeons in clinical practice perform pituitary surgery infrequently, and are unable to develop a sufficient clinical experience associated with improved outcomes [38]. Based on our data, 50 procedures per year appears to represent an acceptable number in PTCOE, thus supporting the previous proposal. In fact, high surgical volume allows surgeons to learn from past experience and apply accumulated knowledge to patient selection, surgical goals, and operative techniques to achieve optimal outcomes and avoid complications, particularly in complex invasive adenomas, reoperations for recurrent adenomas, parasellar giant pituitary adenomas, and pituitary microadenomas in Cushing’s disease that are not visible on MRI [7].
Efficacy and safety are both important quality markers for surgery [38, 39]. Postsurgical remission rates in pituitary adenomas in surveyed centers were similar to those reported in the literature. This may be explained by the fact that only centers with expert surgeons preferentially published in high-quality peer-reviewed journals [40, 41]. However, post-surgical remission rates reported for microadenoma in Cushing’s disease were only slightly lower than in acromegaly, whereas in published series, they have been reported to be either higher, similar, or lower [42, 43, 16, 8, 44, 32, 45]. Data from the surveyed centers may be adversely impacted by the higher percentage of more challenging patients referred from other less specialized centers, where surgeons either did not feel comfortable proceeding with surgery or surgery was not successful in achieving remission.
In a large US survey on 958 neurosurgical complications of pituitary surgery, these occurred significantly more frequently among respondents with less experience [38]. Based on our results, acute side effects of surgery in a PTCOE (including mortality) should be well below 2%, although post-surgical hypopituitarism may be underdiagnosed, particularly GHD [46]. Readmissions rates after pituitary surgery may vary between 7.2% and 8.5% [47–49]. Thus, our validated results show that < 2% of patients with complications should require inpatient readmission within 30 days. This minimally acceptable threshold is also consistent with the literature, although it should be noted that these data may have a selection bias since the most experienced neurosurgeons deal with the most challenging cases, who are at higher risk of developing acute complications [38].
Despite current progress in imaging methods, it can still be challenging to localize a pituitary adenoma, especially in Cushing’s disease [50]. Based on our results, the presence of at least one highly experienced neuroradiologist with a work volume of at least 200 scans a year (and more than 100 contrast MRI per year) is recommended to support the multidisciplinary team. The collaboration with experienced neuroradiologists is also relevant for IPSS when indicated (although quite rarely performed) to differentiate Cushing’s disease from ectopic ACTH-dependent Cushing’s syndrome [51, 52]. The ideal, objective, proposed number of neuroradiologists in our study is 7, whereas a single neuroradiologist is acceptable.
A specialized neuropathology unit is essential to a PTCOE for accurate diagnosis, treatment, and follow-up. At least one pituitary-experienced pathologist with a workload of at least 60 pituitary examinations annually is recommended in a PTCOE to support the clinical team in designing patient-tailored management and optimizing outcomes. Interestingly, assessment of novel molecular markers is not homogeneously available, even among the established PTCOEs surveyed. Therefore, the application of novel molecular techniques, including cell biomarkers, were not included in the current criteria for accreditation of PTCOEs. However, in the future, it is likely that assessment of molecular markers and transcriptions factors will be required in PTCOE.
For patients with pituitary adenomas not controlled by surgery or medical therapy, stereotactic radiotherapy and radiosurgery are safe and effective, albeit used as third-line strategies [16, 8]. In fact, computer-assisted techniques performed by expert radiotherapists in the treatment of intracranial tumors might be used frequently at PTCOEs, offering a fully individualized multimodal therapy option [42, 53–56]. However, in our surveyed centers, conventional radiotherapy has almost completely been abandoned, likely due to a negative risk/benefit balance [55, 57]. Moreover, although the ideal and minimum numbers of dedicated pituitary radiotherapists according to surveyed centers are 3 and 2, respectively; the anticipated numbers of pituitary stereotactic radiotherapy and radiosurgery procedures per year were reported to be 5 and 4, whereas minimal thresholds were 2 and zero; respectively. This may reflect the progressive paradigm shift in the treatment of pituitary adenomas with increasing preference for more effective and well-tolerated medical therapies, as well as radiotherapy. This also raises the question if the requirement of at least two expert radiotherapists in a PTCOE could be reduced to one, given also the progressively reduced availability of experts in the field, since radiotherapy is predominantly employed in oncology practice.
In addition to the recommended support units participating in PTCOEs, the contribution of other specialties is necessary to establish a PTCOE [9]. At least one available experienced neuro-ophthalmologist is required, although in some centers computerized visual field examination is carried out by the endocrinologist, due to the role of visual field defects in diagnosis and follow-up of pituitary macroadenomas, particularly when non-secretory [58], but also when secreting in special conditions (e.g., pregnant woman with macroprolactinoma). On the other hand, progressively more frequent use of chemotherapy for invasive refractory pituitary adenomas [59] would require the presence of at least one neuro-oncologist in a PTCOE.
This study has several limitations as it relied on self-reported data from surveyed centers and did not include an on-site visit. Nonetheless, it is unlikely that highly reputable centers, which volunteered for the study, provided inaccurate data. However, among the difficulties we encountered was a misunderstanding of the purpose of some questions in the survey, which needed clarifications from the Scientific Committee. Therefore, revised responses were obtained from a few centers after data were assessed for inconsistencies and clarification of specific questions. Moreover, questions that required further clarification were identified and reformulated for next steps. The questionnaire did not address unexplored areas, including control rate in medically treated prolactinoma, since this aspect was not considered crucial for a PTCOE definition, being well managed by general endocrinologist [60], according to guidelines [61]. Moreover, side effects of medical treatment [62] or more detail on services important for PTCOE (such as cardiology, neuropsychology, or bone units) [63] were also not recorded. We believe that a compromise should be reached to obtain core information from the centers in a reasonable time frame. Our study demonstrates that with a formulated questionnaire, the accreditation process may require up to eight months for well-organized centers. This period appears reasonable to report current activity data, instead of historical data that may not reflect contemporary situations of evaluated centers.
Numerical criteria were statistically extrapolated from collected data using the median and the worst limit of range as references for establishing ideal and acceptable thresholds. This statistical extrapolation may reflect biases (for example, the number of centers evaluated). However, this methodology allowed us to exclude outliers in terms of larger numbers, potentially raising the bar too high for a realistic definition of PTCOE, applicable globally and to regional initiatives, such as the European Reference Network on rare endocrine conditions (Endo-ERN) in the European Union (EU).
In conclusion, to our knowledge, this is the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort internally validated by ad-hoc reviewers allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived objective model can be used for accreditation of pituitary centers as PTCOEs. As these proposed criteria are transparently discussed and accepted by the scientific community, the structure for managing the accreditation process by the Pituitary Society as an accrediting body would need to be established through a well-balanced, cost-effectiveness analysis. Further steps would optimize the process, such as testing it on a limited number of non-pre-selected centers to assure high standards, objectivity, and transparency. Moreover, these steps will lead to the development of identical databases in all centers and allow a rapid, easy, yearly update while forming a robust basis for research and for possible periodic re-evaluation over time of each PTCOE.