Targeted therapy in BRAF mutated aggressive papillary craniopharyngioma: a case report and overview of the literature.

BACKGROUND: Papillary craniopharyngiomas harbor the BRAF V600E mutation, which paves the way for using BRAF inhibitor molecules to treat tumors refractory to standard therapies. Single case reports confirmed the efficacy of targeted therapy. However, most reports were limited by the short follow-up. We describe the long-term course of a patient treated with dual-agent BRAF and MEK inhibitors and review the available literature. CASE REPORT: A 75-year-old male patient had recurrence of a papillary craniopharyngioma after transsphenoidal surgery and Gamma Knife radiosurgery. Review of the pathologic specimen confirmed the presence of the BRAF V600E mutation. Because of the few therapeutic options, we decided to initiate BRAF/MEK inhibitor combined therapy for six months. Rapid reduction of the tumor occurred, but three months after quitting combined medical therapy the tumor recurred. BRAF/MEK inhibitor therapy was resumed and the tumor again showed a marked reduction. The second course was maintained for 20 months and the tumor showed another recurrence within three months, which, again, responded to a third course of targeted therapy. CONCLUSIONS: Our study confirms the excellent response of papillary craniopharyngioma to combined BRAF and MEK inhibitors. However, rapid tumor recurrence is the rule when medical therapy is stopped. Resistance to a second and third course of targeted therapy did not occur, suggesting that tumor mutations affecting the response to drugs seems an uncommon event in papillary craniopharyngioma. The exact role of targeted therapy in the treatment algorithm of papillary craniopharyngiomas has still to be refined.

Gamma knife radiosurgery is effective in patients with thyrotropin-secreting pituitary adenomas.

PURPOSE: Thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) is a rare cause of TSH-dependent hyperthyroidism. The first therapeutic option is surgery. Medical treatment with somatostatin analogs is also effective. To obviate the need for lifelong drug therapy, gamma knife radiosurgery (GKRS) might be considered in selected patients. We report the largest series of patients with TSHoma treated by GKRS at a single center. METHODS: This study was a retrospective analysis of 18 consecutive patients with TSHoma treated by GKRS between 1994 and 2022. Normalization of hyperthyroidism, when present at the time of surgery, and control of tumor growth were the main outcomes of the study. RESULTS: The median follow-up after GKRS treatment was 114 months (IQR, 57-213 months; range 17-285 months). No patients had growth of the residual tumor after GKRS. Remission of hyperthyroidism occurred in 9 of the 11 (81.8%) patients who were hyperthyroid before GKRS. The probability of hyperthyroidism remission three years after GKRS was 59.1% (95% CI 27.9-90.3%). No major side effects occurred after GKRS. One patient out of the 15 patients (6.7%) with normal baseline adrenal function and follow-up longer than 3 years developed new onset hypoadrenalism, while hypogonadism did not occur in the 13 patients with baseline normal function. CONCLUSION: Our study shows that GKRS is an effective and safe adjuvant treatment for selected patients with residual or recurring TSHoma. The option of GKRS as an alternative treatment to lifelong medical treatment with somatostatin analogs should be thoroughly discussed with the patients.

High prevalence of adrenal cortical adenomas in patients with cerebral meningiomas.

PURPOSE: Adrenal cortical adenomas (ACAs) represent one of the most common endocrine neoplasms. Recently, a genetic syndrome, characterized by tumor-suppressor ARMC5-gene mutations and causing primary macronodular bilateral adrenal hyperplasia with concomitant meningiomas of the central nervous system, has been described. Apart from this rare disorder and despite the well-known influence of steroid hormones on meningiomas, no data are available about the association between ACAs and meningiomas. METHODS: We investigated the prevalence of ACAs in a group of patients with cerebral meningioma undergoing unenhanced chest CT scans before attending surgical treatment. Patients with meningioma were age- and sex-matched in a 1:3 ratio with hospitalized patients for COVID-19. RESULTS: Fifty-six patients with meningioma were included and matched with 168 control patients with COVID-19. One-hundred forty-four (66.1%) were female and the median age was 63 years. Twenty ACAs were detected in the overall population (8.9% of the subjects): 10 in patients with meningioma (18%) and the remaining 10 (6%) in the control group (p = 0.007). Multivariate analysis showed that age and presence of meningioma were statistically associated with the presence of ACAs (p = 0.01, p = 0.008). CONCLUSION: We report, for the first time, a higher prevalence of ACAs in patients with meningioma as compared to age- and sex-matched controls. Larger studies are needed to confirm our data and to clarify the characteristics of the ACAs in patients with meningioma. Whether the detection of ACAs should prompt a neuroimaging evaluation to exclude the presence of meningiomas needs also to be considered.

Gamma knife radiosurgery in patients with Nelson's syndrome.

PURPOSE: Nelson's syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing's disease. The best therapeutic strategy in NS has not been well defined. Gamma knife radiosurgery (GKRS) is very effective to stop the growth of the pituitary adenoma, which is the main goal of the treatment of patients with NS. We report the largest series of patients with NS treated by GKRS at a single center. METHODS: The study was an observational, retrospective analysis of 28 consecutive patients with NS treated by GKRS in our department between 1995 and 2019. All patients had a growing ACTH-secreting pituitary adenoma. The main outcome of the study was to assess by the Kaplan-Meier method the risk of tumor progression after GKRS. RESULTS: The median follow-up after GKRS treatment was 98 months (IQR 61-155 months, range 7-250 months). Two patients (7.1%) had a recurrence of disease during follow-up. The 10-year progression-free survival was 91.7% (95% CI 80.5-100%). No patient had deterioration of visual function or oculomotor function after GKRS. New onset of hypogonadism and hypothyroidism occurred in 18.8% and 14.3% of the patients at risk. CONCLUSION: Our study confirms that GKRS may stop the tumor growth in the majority of patients with NS, even though very aggressive adenomas may ultimately escape this treatment. Safety of GKRS was good in our experience, but due attention must be paid to planning the distribution of radiation to critical structures, especially in patients previously treated by radiation.

The emerging role of hearing loss rehabilitation in patients with vestibular schwannoma treated with Gamma Knife radiosurgery: literature review.

Stereotactic radiosurgery (SRS) is currently the most common treatment for small- to medium-size vestibular schwannoma (VS). Despite favorable outcome, hearing deterioration still remains an underestimated problem, and the role of hearing rehabilitation is an underinvestigated topic. Among available technologies, cochlear implant (CI) should represent a valid alternative in sporadic VS with single-sided deafness and in neurofibromatosis (NF2) with bilateral profound hearing loss. A literature review of the current clinical data was performed searching scientific literature databases. From all of the articles found, 16 papers were selected. Forty-four subjects treated with radiosurgery (18 male, 19 female, and in 7 cases, sex were not specified; 43 NF2 and 1 sporadic VS) were included in the analysis. Epidemiological, clinical, tumor, treatment, and audiological data were collected. Clinical outcome at last follow-up showed an audiological improvement in 25 of the 44 patients. The audiological outcome was unchanged in 16 cases. Audiological deterioration was recorded in 3 cases. Severity of NF2 phenotype, long history of ipsilateral profound deafness before implantation, progressive tumor growth, and high radiation dose (20 and 40 Gy) were found in patients with a worst audiological outcome. Hearing rehabilitation can improve audiological results for VS patients following SRS in selected cases. Hearing rehabilitation with cochlear implant (CI) in SSD leads to partial restoration of binaural hearing with an improvement in speech comprehension in noise and in sound localization, and partial suppression of subjective incapacitating tinnitus. SRS followed by CI may represent in selected cases a potential emerging option in the management of these patients, aimed at improving their quality of life. Possible implications for the follow-up of these patients are still present, although partially resolved.

Primary sellar melanocytoma: pathological, clinical and treatment review.

BACKGROUND: Sellar melanocytomas represent a small subgroup of primary melanocytic tumors. They arise from melanocytes located in the meningeal lining of the sellar floor or in the diaphragma sellae and this location is very uncommon. Usually, sellar melanocytomas are benign and slow-growing tumors with a high likelihood of recurrence. PURPOSE: To our knowledge, due to the rarity of this condition, there are no guidelines regarding their diagnosis and treatment in the medical literature to date. We have developed a narrative review, analyzing the available studies regarding primary sellar melanocytomas reported in the medical literature. We have found ten papers on this topic and all of them are case reports. In all patients, tumor diagnosis was performed after the occurrence of neurological symptoms, in particular progressive visual loss or endocrinological disorders. The diagnosis is difficult, and it requires several preoperative and postoperative investigations, but histological examination is crucial. CONCLUSIONS: Transsphenoidal surgery is the first-choice treatment. In case of tumor's recurrence or regrowth, the role of radiation therapy and chemotherapy is not entirely clear.

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects.

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Vestibular assessment in patients with vestibular schwannomas: what really matters?

Vestibular function is often underdiagnosed in vestibular schwannomas (VS). To evaluate it in a selected group of patients harbouring vestibular schwannomas, 64 patients were included in this study, recruited between March 2008 and June 2011 at our institution. All patients underwent Gd-enhanced MRI and complete neurotological evaluation before gamma knife surgery. Morphological measurements included Koos Classification and quantification of internal acoustic canal filling in length and diameter. Cochlear and vestibular functions were assessed considering pure tone and speech audiometry, bedside examination and caloric test by videonystagmography. A statistical analysis was performed to find possible correlations between morphological and cochleovestibular data. Patients with a higher intracanalicular length (ICL, mean value 8.59 and median 8.8 mm) of the tumour presented a higher value of UW than the subgroup with a lower length (51.9 ± 24.3% and 38.8 ± 18.1% respectively, p = 0.04), while no difference was detected for pure tone audiometry (PTA) values (50.9 ± 22.3 db and 51.1 ± 28.9 db respectively). Patients with a higher ICL also presented a higher rate of positive HIT (88% and 60% respectively, p = 0.006). Patients with a higher value of intracanalicular diameter (ICD, mean value 5.22 and median 5.15 mm) demonstrated higher values of UW (50.2 ± 29.1% and 39.3 ± 21% respectively, p = 0.03), but not different PTA (50.2 ± 29.1 db and 51.9 ± 29.9 db respectively). Finally, patients with a positive head impulse test (HIT) demonstrated significantly higher values of unilateral weakness (UW) (p = 0.001). Vestibular disorders are probably underdiagnosed in patients with VS. ICL and ICD seem to be the main parameters that correlate with vestibular function. Also, in case of small intracanalar T1 VS a slight increase of these variables can result in significant vestibular impairment. The data reported in the present study are not inconsistent with the possibility of proactive treatment of patients with VS.

Review of cerebellopontine angle medulloblastoma.

Cerebellopontine angle (CPA) medulloblastomas (MB) are rare lesions with few cases previously described in the literature. We report two further cases of CPA MB. The patients were a 22-year-old man and a 26-year-old woman with a mass developing in the CPA. The preoperative radiological diagnosis was vestibular schwannoma in the first case and petrosal meningioma in the second case. The patients were operated on through a retrosigmoid approach. The intraoperative findings revealed an intra-axial tumour and the histological diagnosis was classic type of MB in both cases. We review the literature and discuss pathological and radiological features and possible pathogenesis of CPA MB, underlining the necessity to consider MB in the differential diagnosis of CPA lesions.

The role of radiation therapy in the management of non-functioning pituitary adenomas.

Surgical removal of non-functioning pituitary adenoma (NFPA) is the first-choice therapeutic option, but radical removal of the tumor cannot be accomplished in all patients. The best strategy to prevent regrowth of NFPA is still a matter of debate. Adjuvant radiotherapy is very effective in reducing recurrence rate after incomplete removal of NFPA, but concerns still exist about long-term toxicity of radiation. Different modalities have been developed to irradiate the pituitary region. One major distinction is between radiation techniques that deliver the total dose in multiple sessions using 3 fixed radiation beams and radiosurgical equipment that delivers the total dose to the target volume in a single treatment session. Progression-free survival of patients with NFPA treated by adjuvant radiotherapy is well above 90% at 5 yr in most studies and diminishes only slightly at 10 yr. Very few studies have a more prolonged follow-up. In comparison, the 5- and 10-yr estimated recurrence rate without adjuvant radiotherapy ranged from 15% to 51% and from 44% to 78%, respectively. Complications of radiation include rare but severe side-effects, such as secondary brain neoplasm, optic neuropathy, cerebrovascular accidents, and more frequent but less severe complications, such as pituitary deficiency. Optimal management of patients with residual or recurring NFPA after surgical debulking can be achieved through the judicious use of different treatment options, necessitating close cooperation between neurosurgeons, endocrinologists, and radiation oncologists.

A peculiar case of midface reconstruction with four free flaps in a cocaine-addicted patient.

SUMMARY: Cocaine-induced lesions may cause extensive destruction of the osteocartilaginous structures of the nose, sinuses and palate, a syndrome called CIMDL (cocaine-induced midline destructive lesion). In such cases, reconstructive procedures of the lost soft and hard tissues may be indicated, such as local flaps, regional flaps, and free revascularised flaps. Also, prosthetic obturators have been suggested to overcome the functional problems related to the tissue loss. However, the majority of publications are related to relatively small defects, whereas articles related to the surgical treatment of large midfacial defects are less frequently reported. The objective of this article is to report the authors' experience concerning a unique case consisting of a complex reconstruction of a severe cranial base, midface, palate, and nose defect following cocaine abuse with four revascularised flaps followed by prosthetic restoration with implant-supported prostheses.

Thyrotropin-secreting pituitary adenomas: biological and molecular features, diagnosis and therapy.

Central hyperthyroidism due to a thyrotropin (TSH)-secreting pituitary adenoma is a rare cause of hyperthyroidism, representing 0.5-1.0% of all pituitary adenomas. The etiopathogenesis of TSH-secreting-adenomas is unknown and no definite role for various oncogenes has been proven. Patients with TSH-secreting adenoma usually present with signs and symptoms of hyperthyroidism milder than those in patients with hyperthyroidism of thyroid origin, in addition to symptoms secondary to mass effects of the pituitary tumour. Mixed pituitary tumours co-secrete growth hormone and prolactin. The characteristic biochemical abnormalities are normal or high serum TSH concentrations in the presence of elevated total and/or free thyroid hormones concentrations. Measurement of markers of peripheral thyroid hormone action and dynamic tests may aid in the differential diagnosis with the syndrome of resistance to thyroid hormone. Neuroimaging is fundamental to visualize the pituitary tumor. Therapy of TSH-secreting adenomas can be accomplished by surgery, radiation therapies, and medical treatment with somatostatin analogs or dopamine agonists. Nowadays, and in contrast with the first reports on this rare disease, most patients are well controlled by current therapies.

Bi-occipital decompressive craniectomy in refractory post traumatic intracranial hypertension: first report of one case.

Decompressive craniectomy (DC) is considered a 'second tier' therapy to control posttraumatic intracranial hypertension refractory to maximal medical treatment. The authors present a case of refractory intracranial hypertension due to diffuse brain swelling and a large (>25 ml) non-surgically-treatable haematoma of the splenium of the corpus callosum successfully treated with bi-occipital DC and augmentative duraplasty.

Complications of transsphenoidal surgery in patients with pituitary adenoma: experience at a single centre.

OBJECTIVE: This paper reports the complications of transsphenoidal surgery for pituitary adenomas in a series of 1240 consecutive patients operated at our Institute between 1990 and 2004 (first operations) and indicate the clinical characteristics of patients which affected surgical morbidity and mortality. METHODS: According to tumour type, there were 420 (33.9%) non-functioning pituitary adenomas (NFPA), 349 (28.1%) GH-secreting, 288 (23.2%) ACTH-secreting, 155 (12.5%) prolactin (PRL)-secreting, and 28 (2.3%) TSH-secreting adenomas. The mean age of patients was 43.7 +/- 0.4 yr and 122 patients (9.9%) were 65 yr or older; the female/male ratio was 1.5/1. There were 370 (29.8%) microadenomas and 870 (70.2%) macroadenomas of which 54 (4.4%) were giant adenomas. RESULTS: The series mortality was 0.2%, the medical morbidity 1.9%, and the surgical morbidity 3.5%. Medical complications were significantly more frequent in patients older than 65 yr (4.9 vs. 1.4%; p = 0.009) and in patients with giant adenomas (5.6 vs. 1.6%; p = 0.03). Multivariate analysis showed that both variables were independently associated with a higher morbidity rate. The surgical morbidity was increased in giant adenomas (15 vs. 3%; p = 0.0001), in NFPA (6.2 vs. 2.1% in secreting adenomas; p = 0.0002) and in patients older than 65 yr (6.6 vs. 3.1%; p = 0.05). Multivariate analysis showed that only giant size was independently associated with an increased surgical morbidity rate. CONCLUSIONS: In our experience, the size of the adenoma was a risk factor for medical and surgery related complications and age over 65 yr for medical complications alone.

Intrasellar paraganglioma: a case report and review of the literature.

Intrasellar paragangliomas are very rare lesions with only six previous cases described in the literature. We present a further case of intrasellar paraganglioma. The patient was a 52 yr-old man who developed two transient ischemic attacks. A CT scan showed an intra- and supra-sellar expanding lesion, which was regarded as a possible non-functioning pituitary macro-adenoma. Removal of the lesion was accomplished by transsphenoidal surgery. Histological examination was diagnostic of a paraganglioma. We review the literature and discuss pathological features and possible pathogenesis of sellar and parasellar paragangliomas, underlining the necessity to consider paraganglioma in the differential diagnosis of sellar lesions.

Coexistence of TSH-secreting pituitary adenoma and autoimmune hypothyroidism.

OBJECTIVE: TSH-secreting pituitary adenomas account for about 1-2% of all pituitary adenomas. Their diagnosis may be very difficult when coexistence of other diseases masquerades the clinical and biochemical manifestations of TSH-hypersecretion. CLINICAL PRESENTATION: A 41-yr-old female patient, weighing 56 kg, was referred for evaluation of an intra- and suprasellar mass causing menstrual irregularities. Eight yr before, the patient had been given a diagnosis of subclinical autoimmune hypothyroidism because of slightly elevated TSH levels and low-normal free T4 (FT4). Menses were normal. Despite increasing doses of levo-T4 (L-T4; up to 125 microg/day), TSH levels remained elevated and the patient developed mild symptoms of hyperthyroidism. After 7 yr, the menstrual cycle ceased. Gonadotropins were normal, whereas PRL level was elevated at 70 microg/l and magnetic resonance imaging (MRI) of the hypothalamic- pituitary region revealed a pituitary lesion with slight suprasellar extension. The tumor was surgically removed and histological examinations revealed a pituitary adenoma strongly positive for TSH. Three months after surgery the patient was well while receiving L-T4 75 microg/day and normal menses had resumed. MRI of the hypothalamic-pituitary region showed no evidence of residual tumor. At the last follow-up, 16 months after surgery, serum TSH, free T3 (FT3), and FT4 levels were normal. CONCLUSIONS: Coexistence of autoimmune hypothyroidism and TSH-secreting pituitary adenoma may cause further delays in the diagnosis of the latter. In patients with autoimmune hypothyroidism, one should be aware of the possible presence of a TSH-secreting pituitary adenoma when TSH levels do not adequately suppress in the face of high doses of L-T4 replacement therapy and elevated serum thyroid hormone levels.

A non-functioning pituitary adenoma initially mimicking a microprolactinoma: The case for long-term follow-up of patients with mild hyperprolactinemia?

OBJECTIVE: A correct differential diagnosis of patients with mild hyperprolactinemia is essential to select the most appropriate treatment modality. CLINICAL PRESENTATION: A 50-yr-old woman presented to our Department for evaluation of an intra- and suprasellar mass causing progressive visual defect. Mild hyperprolactinemia causing menstrual irregularities was diagnosed in February 1989. In 1992, serum PRL levels ranged from 50 to 70 microg/l and magnetic resonance imaging (MRI) of the hypothalamic-pituitary region showed the presence of a 7 mm microadenoma. Bromocriptine therapy resulted in normalization of PRL levels and menstrual cycle, while a repeat MRI showed no change. Menses stopped in March 1998, when the patient was 46 yr old. Subsequently, the patient complained of worsening headaches and, starting from July 2001, visual disturbances. In March 2002, MRI showed a large pituitary tumor, measuring 40x37x28 mm. In May 2002, the patient was operated through the transsphenoidal approach with apparent total tumor removal. Histological examination confirmed a pituitary adenoma that stained negative for all pituitary hormones. Four months after surgery, the patient reported an improvement of visual function. MRI of the hypothalamic-pituitary region, performed 4, 13 and 25 months after surgery, showed a partially empty sella with no evidence of residual tumor. CONCLUSIONS: This case suggests that, to exclude the alternative diagnosis of nonfunctioning pituitary adenoma or another mass lesion of the hypothalamic-pituitary region, repeat neuroimaging studies during long-term follow-up may be advisable in patients with presumed microprolactinoma who did not show reduction of the tumor during dopaminergic therapy.

Correlation between clinical characteristics and proliferative activity in patients with craniopharyngioma.

OBJECTIVES: The aim of the study was to correlate the Ki-67 and cyclin A labelling index (LI) with clinical characteristics and risk of recurrence of craniopharyngiomas. METHODS: 47 consecutive patients were studied, 21 female and 26 male, aged 34.3 (2.8) years. Immunohistochemical analysis was performed on paraffin wax embedded material using monoclonal antibodies directed against the proliferation associated nuclear antigen Ki-67 and cyclin A. RESULTS: The median Ki-67 LI was 8.6% (interquartile range, 4.4%-14.0%). Ki-67 LI was significantly higher in tumours with a heavy inflammatory reaction and diabetes insipidus at presentation, whereas other clinical and histological features were not associated with the proliferation index. There was a strong linear correlation between Ki-67 LI and cyclin A LI (r = 0.77; p<0.0001); therefore, cyclin A LI showed the same clinical and histological relations described for Ki-67 LI. Recurrence of craniopharyngioma occurred in 13 of 46 patients (28.3%). The median Ki-67 LI in the 13 recurrent craniopharyngiomas (9.0%) was not significantly different from that of non-recurring tumours (7.9%). Cyclin A LI was also not associated with the risk of relapse. CONCLUSIONS: This study confirms the great variability of proliferative activity in craniopharyngiomas. Ki-67 and cyclin A LIs were associated with the presence of a heavy inflammatory reaction and diabetes insipidus, but did not correlate with the long term risk of tumour regrowth.