India's March towards Development of Treatment for Pituitary Tumors
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.299156
Source of Support: None, Conflict of Interest: None
Keywords: Gamma knife radiosurgery, India, pituitary adenoma, sellar-supra sellar
Although pituitary adenomas (PA) are classically considered benign, the extent and the pathological variations often make management difficult. The autopsy and radiological studies have shown a prevalence of 17% in the general population that account for disability-adjusted life of years (DALYs) and lost years of life lived with disability (YLD). The most notable morbidities are visual deficits and hormonal imbalances. Sellar supra sellar tumors have the highest burden of neuropsychological symptoms and hypopituitarism amongst patients of pituitary tumors., This has major repercussions on the country health system especially considering the fact that most of the patients are between the second and fourth decade which are the most productive periods of life. The transition from microscopic to endoscopic and to neuronavigation has significantly improved the outcomes of pituitary surgery. In this article, we present the current scenario of pituitary research in India, major challenges, and efforts for arresting sellar-suprasellar disease burden.
While Daly et al., Lee et al. and Park et al. reported low prevalence of 0.09% in Leige, Belgium, and 0.04% in Korea, respectively,,, Katsura et al. reported high prevalence of 13.8% (in 1959) in Japan. In India, the prevalence in Rajasthan was 7.6%. Unfortunately, no nationwide prevalence and incidence data is available from Indian cohort.
In a study by Bhuyan M et al., clinicopathological characteristics and proportion of various hormones in pituitary adenomas were determined in the Northeast Indian population by analyzing surgically resected and immunohistochemically evaluated pituitary macroadenomas. In this study, tumors were resected by either of the two techniques; trans-sphenoidal microsurgery or endoscopic endonasal approach to the sella using the paraseptal, middle meatal, or middle turbinectomy approach. Tumors were mainly found in the young adult population with a mean age of 38.12 years with a female preponderance. Totally, 40.6% of PA were non-functioning and among the hormonally active PA, Prolactin (PRL) producing (25%), Growth Hormone (GH) producing (18.8%), and Adrenocorticotropic (ACTH) producing adenomas (15.6%) were common. Ectopic Cushing's syndrome is a rare disease with varied manifestations associated with increased morbidity and mortality. The clinical features of ectopic Cushing's are quite similar to classical Cushing's with surgery being the treatment of choice.,
Age, gender, and tumor size
In a study by Dutta P et al. from India, the mean age at diagnosis was 37.1 ± 12.3 years whereas the mean age reported from Swedish population was 50.7 ± 12.3 years. There was a clear bias towards patients age (>50 years) and patient's gender (generally fewer women than men). The pediatric giant pituitary adenomas are rare, more aggressive, and majorly functional in comparison to adults. The pre-operative mean tumor volume reported from India is 6.81 ± 5.81 cm3 whereas it was 24.66 cm3 in USA., A study by Haliloglu O et al. from Istanbul reported that out of 103 pituitary adenomas, 32% and 68% were micro and macroadenomas, respectively. A multidisciplinary approach by an experienced and dedicated team is necessary to achieve the best remission rates due to the complexity of the disease. According to a study by McDowell DB et al., median tumor size of Asian/Pacific Islanders was 20 mm3 (IQR = 20). The racial preference for primary surgery was also observed in which Asian/Pacific Islanders (69%) were most likely to prefer surgical intervention. Macroprolactinomas are observed equally prevalent in both the genders. Moreover, macroprolactinomas in males predominantly present with larger tumor size and symptoms of mass effects, as against females who present with symptoms of hypogonadism. There is an increasing evidence of pituitary adenoma heterogeneity between different populations, but there is very limited data from India.
Most of the genetic causes of Acromegaly in our experience are either McCune Albright, Multiple endocrine neoplasia, type 1 (MEN-1) or Aryl hydrocarbon receptor-interacting protein (AIP) mutation. The likelihood of AIP mutation increases if a patient has a history of isolated pituitary adenoma or if the disease onset happens in the second decade of life accompanied with macroadenoma and apoplexy. In patients with MEN-1 mutation or features of MEN-1, the pituitary adenoma most often found is somatotropinoma, prolactinoma, and nonfunctioning pituitary adenoma in descending order. The other common association is primary parathyroid followed by neuroendocrine tumors of gut, gastrinoma, carcinoid, and insulinoma.
At present, the standard of care for a pituitary adenoma involves primary surgical intervention followed by radio surgical management of the residual/recurrent tumor with or without chemotherapy. Surgery remains the primary and the best treatment option as it provides immediate reduction of the tumor burden, decompression of the visual apparatus and the hypothalamic pituitary axis, histopathological characterization of the tumor, and the best normalization of the endocrine status. If removed completely, as mostly in Knosp grade 1-3 tumors, there is no need for any adjuvant treatment modality. Prolactinomas are the commonest of the functioning pituitary adenomas. Medical management of prolactinomas forms the mainstay of treatment. Pharmacological agents to treat hyperprolactinemia are dopamine agonists as well as the serotonin antagonist metergoline.
The two main surgical approaches are transcranial surgery and the less invasive transsphenoidal surgery (TSS), which is now preferred by most neurosurgeons. The choice of each of these modalities depends on the type of tumor, aggressiveness or invasion, the extent of tumor removal and surgeons expertise. A relatively recent advancement is supraorbital eyebrow craniotomy for sellar-parasellar tumors. The supraorbital craniotomy with endoscopic assistance is an effective tool for removal of anterior and middle cranial fossa extra axial and intra axial pathologies. It is an approach for the sellar tumors particularly with far lateral and suprasellar extensions. It provides a minimally invasive access to the lesions with greater extension.
Despite improvement in surgical technique, visualization, better surgical armamentarium such as different angled endoscopes and intraoperative MRI, the chances of gross total resection for various PA are only up to 67–70%, especially in tumors Knosp grade 3 or more. This leaves a remnant in one third to one fourth of the patients primarily treated with surgery. A residual tumor is a potential threat posing risk of lower chances of progression free survival and long-term endocrinological failure. Focused stereotactic radiosurgery is a useful radiation adjuvant. The Gamma knife Radiosurgery (GKRS) is a non-invasive treatment for treating pituitary tumors. The gamma knife surgery treatment involves high precision of dose delivery, durability, and accuracy along with operational ease. Adjuvant GKRS not only provides a safe progression free outcome but also good endocrinological outcome. With the availability of fractionated GKRS, even the residual tumors in close vicinity of the optic apparatus can be safely treated. A primary GKRS is also considered a valid treatment option for medically infirm patients or patients unwilling for surgical interventions. Other forms of radiation techniques such as intensity modulated radiation therapy (IMRT) should only be used in patients with no gap of the optic apparatus from the tumor, large tumor volume, or non-availability of GKRS techniques. Less often used is pituitary irradiation, mainly because of its slow onset of effects and near confirmed hypopituitarism. Progress in the diagnostic examination of pituitary adenomas and advances in the treatment of these tumors offer excellent prospects for a successful therapeutic outcome.
Among neurosurgeons, there is an increasing trend to advise adjuvant stereotactic radiosurgery for residual/recurrent pituitary adenomas. A proactive GKRS for a residual NFPT helps in progression free survival that significantly curtails the chances of future surgeries. Any GKRS after a documented increase in the tumor volume on repeat follow up imaging provides nearly similar progression free survival but at the cost of higher risk of endocrinological failure. For functional pituitary adenomas, hormonal control gets preference to volumetric control and proactive GKRS helps in achieving this goal in lesser time and with lesser complication profile. Similar practices are also observed at smaller non-institutional and private centers across the country.
The treatment and surgery for pituitary lesions costs in India are comparatively lower than high income countries. This prevents high out-of-pocket expenditure and regains control while opting for private hospitals. The surgeons and healthcare professionals in India are extremely talented. Cities offering Pituitary tumors treatment in India are Delhi, Mumbai, Hyderabad, Kerala, Pune, Goa, Bangalore, Nagpur, Jaipur, Chennai, Gurgaon, and Chandigarh. All the major hospitals are equipped with state of the art facilities and highly specialized team of doctors trained with modern technology. India gives the opportunity to have high class immediate surgical and medical treatments which include pituitary tumor treatment and surgery at low cost.
Endoscopic neurosurgery has made a paradigm shift in the management of pituitary adenomas in the last decade. This trend is uniform in India and the world. Transsphenoidal surgeries are associated with lower cost of the treatment, shorter hospital stay, and better morbidity and mortality profile compared to the transcranial surgeries. Transcranial surgeries are still practiced at low volume centers with scant availability of the endoscopic expertise. The low volume centers are also found to have adverse economic outcome.
The Gamma knife Radiosurgery is available at All India Institute of Medical Sciences (AIIMS, New Delhi), Postgraduate Institute of Medical Education and Research (PGIMER, Chandigarh), National Institute of Mental Health and Neurosciences (NIMHANS, Bangalore), Vidya Sagar Institute of Mental Health and Neurosciences (VIMHANS, New Delhi), Research & Referral hospital (R&R, New Delhi), and Hinduja Hospital, King Edward Memorial Hospital, Tata Memorial Hospital and JJ Hospital (Mumbai) in India. The Gamma Knife has different versions of the machine and the Perfexion (the second latest version) is available at PGIMER, AIIMS, & R&R hospital. The cost of treatment at AIIMS, Delhi, and PGIMER, Chandigarh is INR 75,000 (USD 1087) while at NIMHANS is INR 100,000 (USD 1450). The R & R hospital caters services to the patients from the armed forces in India. Surgery cost at a Government setup ranges from INR 50,000 to 70,000 (USD 725 to 1015) whereas cost at a private centers ranges from INR 200,000 to 250,000 (USD 2900 to 3620). The treatment of patients holding a valid BPL card (Below poverty line) is free at Government hospital (PGIMER, Chandigarh and AIIMS New Delhi). The treatment cost in India is less as compared to treatment cost reported in USA (USD 13,708) and Netherlands (USD 3418).,,,,,, As such patients are being primarily managed by tertiary care hospitals in tier A and B cities, a patient may need to visit many times which adversely affects the functional output and DALY. An important aspect of the management of a functional pituitary adenoma is an understanding that the patient may need a life-long follow up or multiple treatment sessions. There are wide variations in the cost of the treatment if the patient gets a treatment in government set up versus corporate hospital. With better government policies and insurance coverage, most of the patients are now able to afford the cost of the treatment.
Although most pituitary adenoma research is conducted in high-income countries, yet most pituitary adenoma cases are observed in low- and middle-income countries (LMIC). There is an urgent need to build pituitary adenoma registry research capacity in LMIC. A literature search was conducted using the following key words: Pituitary adenoma, pituitary tumor, acromegaly, Cushings Disease, non-functioning pituitary adenoma, sellar-supra sellar disorders, and India. An analysis of the total number of publications from India listed in PubMed from 1985 to 2020 revealed that 692 papers related to sellar and supra-sellar/pituitary adenoma research which is gradually increasing over time, although this is considerably less as compared to the publications from the rest of the world [Figure 1] and [Figure 2].
The significant challenges faced by patients in developing countries in treating this benign disease are (i) lack of awareness of the disease (ii) lack of brain imaging facility in rural areas of India (Several cases remain undiagnosed due to lack of imaging facility) (iii) poor patient follow up, and (iv) financial constraints which prevent periodic imaging. Pituitary Apoplexy is a medical emergency with a possible surgical indication; any delay in treatment causes significant morbidity and even mortality. An early assessment and treatment through proven hospital-based interventions remain a major obstacle.
Other than allopathic medicine, varied forms of the scientifically appropriate and acceptable system of indigenous medications such as the Ayurveda, Yoga, Naturopathy, and Homeopathy (AYUSH) system are being practiced in different parts of India. The National Rural Health Mission has decided to strengthen the healthcare delivery system by mainstreaming AYUSH system. However, no study has reported alternative treatment specific for pituitary lesions. There is no level of evidence of the safety, and efficacy of any alternative treatment modality for pituitary adenomas.
Because Indian patient characteristics are different from the western counterpart, there is a dire need for country-specific research to formulate patient treatment and management guidelines. A multi-disciplinary team involving endocrinologist, neurosurgeon, gynecologist, anesthesia, histopathologist, and psychiatrist can achieve a better cure rate. Data on the type of research, basic, clinical, biochemical, endocrinological, histopathology, etc., would be very helpful. It would be cost effective to develop a dedicated surgical team focused on management of pituitary disorders, as administration of a prolonged medical therapy in the event of treatment failure is often unaffordable. Cross talk between basic scientist and clinicians would promote high-quality research in India. Similar to the John Hopkins Pituitary Center or the Pituitary Tumor Centers of Excellence (PTCOE), India too needs Centre of Advance Research and Excellence with state-of-the-art facility for surgery, research, training, and patient care. Research training opportunities can be developed locally, or internationally, with several national and international schemes available to help support new researchers from LMIC settings. International collaboration can successfully leverage funding from high-income countries that not only generate data for the local country but also provide new data appropriate to high-income countries. The collaborative work will help in improvement of infrastructure and training the research coordinators, improvement in the quality of care, data collection and data sharing and higher impact factor publication. Moreover, a clinical, technology and management emersion can help to tackle the health needs of the country and reach the marginalized population in remote areas.
Genetic screening and testing in sporadic pituitary adenomas and family members in the early stage of the disease will ultimately lead to better outcome. Genetic testing can help in better patient management and proper counseling of family members. Family members of Acromegaly, Prolactinoma and Cushing's diseases should be screened to exclude familial disorders. Also, newer medications or multimodality treatment are needed to face the ever growing challenges.,,,
A computerized pituitary registry is required to collect comprehensive demographic, therapeutic, and pathologic data and outcome information of patients living with these tumors. The registry would improve early identification of recurrent patients, strategies to manage aggressive tumors effectively, and long-term outcomes, not only of the pituitary tumors, but also of the systemic illnesses arising due to them. The data from the registry will help in making policy level shift in focus.
We would like to thank Late Prof. KK Mukherjee, Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India and all our patients for being our biggest encouragement to work hard in better patient management and developing new treatment modality for pituitary adenomas.
All authors have contributed equally.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]