Purpose
Pregnancy is associated with the activation of the hypothalamus–pituitary–adrenal axis, which can cause a misdiagnosis of Cushing’s syndrome. The aim of this study is to evaluate the impact ...of pregnancy after pituitary surgery on the recurrence rate in Cushing’s disease (CD) patients.
Methods
This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14–45), PS remission, a follow-up of ≥6 months (median of 122 months, 6–402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing’s syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA).
Results
Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses.
Conclusions
There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data.
Purpose
Cushing’s disease (CD) is a severe illness generally caused by microcorticotropinomas (MICs) and in approximately 7–20% of patients by macrocorticotropinomas (MACs).
USP8
-mutations have been ...identified as a major genetic cause of CD (~ 50%). Few studies have reported the distribution between MICs–MACs related to
USP8
-mutations and their genotype–phenotype correlations. Therefore, we aimed to evaluate
USP8
-mutations in a cohort of MICs–MACs from a unique center and to perform a systematic review and meta-analysis.
Methods
DNA-tumor-tissues from 47 corticotropinomas (16 MICs and 31 MACs) were sequenced. Clinical-biochemical data, radiological imaging data and remission/recurrence rates were evaluated. In addition, we performed a meta-analysis of nine published series (n = 630).
Results
We identified four different
USP8
-mutations previously described, in 11 out of 47 (23.4%) corticotropinomas; 8 out of 11 were MACs. The urinary cortisol levels of our patients with corticotrophin
USP8
-mutated-alleles were lower than those of patients with wild-type (WT) alleles (
p
≤ 0.017). The frequency of
USP8
-mutated-alleles among the series was approximately 30% with a higher prevalence in female-patients (
p
< 0.1 × 10
−4
). Among the 5 series, the remission rates were higher in patients with
USP8
-mutated-alleles than in those with the
USP8
-WT-alleles (
p
< 0.1 × 10
−4
).
Conclusion
Our data, as well as the retrospective review of CD series associated with
USP8
-mutated alleles, show heterogeneous findings among the series. Several drawbacks included the lack of a systematic protocol to evaluate these patients before surgery and follow-up. Further prospective studies using a systematic protocol will provide more consistent information about the influence of the corticotropinomas with
USP8
-mutated alleles on the phenotype, responses to treatment and outcome of patients with CD.
We present the unique case of an adult Brazilian woman with severe short stature due to growth hormone deficiency with a heterozygous G to T substitution in the donor splice site of intron 3 of the ...growth hormone 1 (
) gene (c.291+1G>T). In this autosomal dominant form of growth hormone deficiency (type II), exon 3 skipping results in expression of the 17.5 kDa isoform of growth hormone, which has a dominant negative effect over the bioactive isoform, is retained in the endoplasmic reticulum, disrupts the Golgi apparatus, and impairs the secretion of other pituitary hormones in addition to growth hormone deficiency. This mechanism led to the progression of central hypothyroidism in the same patient. After 5 years of growth and thyroid hormone replacement, at the age of 33, laboratory evaluation for increased weight gain revealed high serum and urine cortisol concentrations, which could not be suppressed with dexamethasone. Magnetic resonance imaging of the sella turcica detected a pituitary macroadenoma, which was surgically removed. Histological examination confirmed an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma. A ubiquitin-specific peptidase 8 (
) somatic pathogenic variant (c.2159C>G/p.Pro720Arg) was found in the tumor. In conclusion, we report progression of isolated growth hormone deficiency due to a germline
variant to combined pituitary hormone deficiency followed by hypercortisolism due to an ACTH-secreting macroadenoma with a somatic variant in
in the same patient. Genetic studies allowed etiologic diagnosis and prognosis of this unique case.
Although craniopharyngioma (CP) is histologically benign, it is a pituitary tumour that grows rapidly and often recurs. Adamantinomatous CP (ACP) was associated with an activating mutation in ...β-catenin, and it has been postulated that pituitary stem cells might play a role in oncogenesis in human ACP. Stem cells have also been identified in pituitary adenoma. Our aim was to characterize the expression pattern of ABCG2, CD44, DLL4, NANOG, NOTCH2, POU5F1/OCT4, SOX2, and SOX9 stem cell markers in human ACP and pituitary adenoma.
We studied 33 patients (9 ACP and 24 adenoma) using real-time quantitative PCR (RT-qPCR) and immunohistochemistry. SOX9 was up-regulated in ACP, exhibiting positive immunostaining in the epithelium and stroma, with the highest expression in patients with recurrence. CD44 was overexpressed in ACP as confirmed by immunohistochemistry. SOX2 did not significantly differ among the tumour types. The RT-qPCR array showed an increased expression of MKI67,OCT4/POU5F1, and DLL4 in all tumours. NANOG was decreased in ACP. ABCG2 was down-regulated in most of the tumours. NOTCH2 was significantly decreased in the adenomas.
Our results confirm the presence of stem cell markers in human pituitary tumours as well as the different expression patterns of ACP and adenoma. These findings suggest that ACP may originate from a more undifferentiated cell cluster. Additionally, SOX9 immunodetection in the stroma and the highest expression levels related to the relapse of patients suggest a contribution to the aggressive behaviour and high recurrence of this tumour type.
Purpose
To analyze the bilateral and simultaneous petrosal sinus sampling (BIPSS) in a subgroup of children and adolescents with ACTH-dependent Cushing’s syndrome (ADCS)
Methods
Retrospective study ...in a tertiary reference center. From 1993 and 2017, 19 children and adolescents (PED) were submitted to the BIPSS, median age of 14 years (range 9–19 years), 53% were males, 18 had Cushing’s disease (CD) and one had ectopic ACTH syndrome (EAS). All procedures were performed with 10 µg of intravenous desmopressin.
Results
The catheter positioning was successful in all cases. The central ACTH gradient was met in 17/19 cases. At baseline, central gradient occurred in 16/19 (84%) with gradient values of 7.2 ± 6.0. After stimulation, there was an increase in the center-periphery gradient values (33.6 ± 44.3). In one case, central gradient was defined only after stimulation. Two cases presented without a central gradient; one case of CD with a false-negative and one EAS case. Lateralization occurred in all cases with a central gradient. Confirmation of the tumor location presumed by the procedure with the surgical description occurred in 60% of the cases. The BIPSS in this PED subgroup of ADCS presented a sensitivity of 94.4% and specificity of 100%. There were no complications of the procedure.
Conclusion
In a series of children and adolescents with ADCS, BIPSS was safe and highly accurate in defining the central to peripheral ACTH gradient using desmopressin as secretagogue. Nevertheless, there was a limited value of the ACTH-gradient between the petrosal sinuses for the tumor location.
Purpose
Dopamine agonists (DA) are the gold-standard for prolactinoma and hyperprolactinemia treatment. Intolerance to DA leading to drug drop out occurs in 3 to 12% of cases. We provide here a ...review of published data about DA intolerance and present a case report concerning the use of intravaginal cabergoline.
Methods
We review the literature on the definition, the pathogenesis, frequency and management of DA intolerance. In addition, the review provides strategies to enhance tolerability and avoid precocious clinical treatment withdrawal.
Results
Cabergoline is often cited as the most tolerable DA and its side effects tend to ameliorate within days to weeks. Restarting the same drug at a lower dose or switching to another DA can be used in cases of intolerance. The vaginal route can be tried specifically if there are gastrointestinal side effects in the oral administration. Symptomatic treatment could be attempted, although mainly based on a strategy used in other diseases.
Conclusions
Due to limited data, no guidelines have been developed for the management of intolerance in DA treatment. The most frequent management is to perform transsphenoidal surgery. Nevertheless, this manuscript provides data derived from published literature and expert opinion, suggesting new approaches to this clinical issue.
The cyclicity (CIC) of cortisol spontaneously occurs in a minority of patients with Cushing syndrome (CS). When it arises, diagnostic and therapeutic approaches become more challenging. This study ...aimed to report a patient with Cushing disease (CD) who achieved normalization of cortisol and CIC pattern with pasireotide long-acting release (pasi/LAR).
A 43-year-old female patient related an 8-month history of CS. An 8-mm pituitary nodule depicted by magnetic resonance imaging, serum cortisol suppression of >50% after 8 mg of dexamethasone therapy, and the absence of other lesions were compatible with a CD diagnosis. The patient presented with a CIC pattern with 1 episode before and 17 episodes after an unsuccessful pituitary surgery.
Medical treatment with cabergoline alone up to 3.5 mg/wk and a combined treatment with ketoconazole 400 mg/d did not improve CIC CS. Pasi/LAR was initiated at a dose of 20 mg/mo. A few days after the first dose, the patient experienced symptoms suggestive of adrenal insufficiency. The medication and dose were maintained for 24 months. During this period, there was a normalization of UFC levels and progressive clinical improvement. Additionally, new episodes of CIC were not observed.
A CD patient with a challenging issue of CIC was reported. The condition was not controlled after pituitary surgery and by the combined treatment with cabergoline and ketoconazole, although hypercortisolism was abated by the continuous use of pasi/LAR. To our knowledge, this is the first report as regards the use of this medication to control CIC in a patient with CD.
Pituitary carcinomas are very rare tumors that in most cases produce prolactin and adrenocorticotropic hormone (ACTH). It is a challenge to diagnosis of a pituitary carcinoma before disclosed ...symptomatic metastasis. We report the case of a female patient with Cushing’s disease who underwent three transsphenoidal surgeries, with pathological findings of common ACTH pituitary adenoma including Ki-67 expression <3%. She achieved hypocortisolism after the 3rd surgery although ACTH levels remained slightly elevated. The patient returned some time later with fast worsening of hypercortisolism. Magnetic resonance imaging showed clivus invasion, which led to a fourth surgery and radiation. This time, immunohistochemistry revealed strong Ki-67 (10% to 15%) and p53 expression. Liver and lumbar spine metastases were found on workup. The patient died after few months due to lung infection. Pituitary carcinomas are rare, and the transformation of an ACTH-secreting pituitary adenoma into a carcinoma is exceptional. The difficulty of defining markers for the diagnosis of carcinoma, before metastasis diagnosis, in order to change the management of the disease, is a challenge.
Abstract
BACKGROUND: Dopaminergic agonist cabergoline (CAB) has been used in pharmacological treatment of Cushing’s disease (CD). The effect is attributed to the frequent expression of subtype 2 ...dopamine receptor in corticotropic tumors. However, in vivo studies demonstrated normalization of urinary cortisol (UC) in about 30-40% of cases over the long term, mainly after surgical failure. Objective: To evaluate the effect of CAB as monotherapy in early preoperative period and on recurrence of Cushing’s disease. Methods. A single-center retrospective study was conducted in a tertiary referral center. Twenty-one patients with confirmed CD were included. Median age was 32 years (13-70), 86% female, 10 with microadenomas, 11 with macroadenomas. They were diagnosed from 1986 to 2016 and used CAB as monotherapy either in the preoperative period (n=7, CABi) or in recurrence, before any other treatment (n=14, CABr). It was considered ‘complete response’ a 24h-UC normalization and ‘partial response’ a 24h-UC reduction >50%. UC was obtained on the last follow-up evaluation. Normalization of nocturnal salivary cortisol (NSC) on CAB was evaluated in most cases, as well as the larger tumor diameter by pituitary MRI, before and after CAB treatment. Results: Complete response was achieved in 29% (6/21) of subjects after 14.9±16.4 months of treatment with a mean dose of 2.2±1.0 mg/wweek. Partial response occurred in 9.5% (2/21). NSC normalized in 35% (6/17) and no variation in tumor diameter before and after CAB use was observed (n=13): 6.8±6.8 vs. 7.2±7.1 mm, respectively. There was no normalization of UC in CABi at the end of the treatment whereas in CABr, 43% (6/14) of patients reached complete response. CABi group was treated for 4.7±1.9 months and CABr was treated for 20.1±18.1 months. Both groups were on similar doses of CAB (CABi 2.1±0.9 and CABr 2.3±1.1 mg/w). Interestingly, the difference between the groups’ complete response was evident early on 3 months of treatment: no cases in CABi vs. 60% (6/10) in CABr (p=0.035) despite a lower dose in CABr (1.0 vs. 1.5; p=0.008). Normalization of NSC occurred in 20% in CABi and 42% in CABr. Conclusion. Normalization of UC and NSC occurred in about 30% of total patients, mainly those who used CAB on recurrence of CD. Due to the small number of subjects in CABi group, the absence of hormone control in this group requires further investigation in order to verify the effectiveness of CAB as primary therapy or as preoperative treatment option.
Adenomas hipofisários são tumores benignos, de crescimento lento, originados no interior da sela túrcica e constituem de 10% a 15% dos tumores intracranianos, Os adenomas clinicamente não ...funcionantes (ACNF), correspondem aproximadamente um terço dos adenomas em geral. Por não apresentarem síndrome clínica hormonal são geralmente diagnosticados devido a sintomas neurológicos ou oftalmológicos, como macroadenomas, com grandes dimensões, invasão de estruturas circunvizinhas e hipopituitarismo. A cirurgia é o tratamento de escolha para estes tumores e apesar de ser eficaz na resolução do quadro compressivo, a possibilidade de cura cirúrgica é reduzida principalmente em tumores invasivos. Seu acompanhamento pós-operatório é efetuado por exame de imagem, preferencialmente ressonância magnética, devido à indisponibilidade de marcadores séricos. Nesta pesquisa avaliou-se a relação da expressão dos genes relacionados à apoptose, Bcl-2, Bax e Caspase-3 e sua relação com o comportamento dos ACNF. Na Divisão de Neurocirurgia Funcional do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo foram operados 119 doentes com tumores hipofisários, de 28/05/08 à 07/04/09, 50 deles com ACNF, 30 deles foram estudados. A ressonância magnética da região selar pré-operatória possibilitou a medida dos três maiores diâmetros do tumor, ou seja, antero-posterior (AP), crânio-caudal (CC), látero-lateral (LL) e avaliar a invasão do seios cavernoso e esfenoidal. O tamanho dos tumores foi avaliado pela soma dos três diâmetros, pelo maior diâmetro e pelo cálculo do volume, efetuado pela fórmula AP x CC x LL x 0,5. No intraoperatório foram avaliados, a consistência e invasão tumoral. A análise histológica por hematoxilina-eosina, foi efetuada em todos os tumores, assim como a análise imuno-histoquímica (IHQ) dos hormônios hipofisários, Ki-67, p53 e Bcl-2. Foi realizada a análise molecular dos genes Bcl-2, Bax e Caspase-3 por RT-PCR. Dados demográficos: 17 do sexo masculino, 13 do sexo feminino, mediana da idade foi de 54,5 anos e mediana da duração dos sintomas de 31 meses. Todos apresentavam macroadenoma, 87% deles com perda visual, 53% com cefaléia, 17% com outras alterações neurológicas e um assintomático diagnosticado incidentalmente. Avaliação hormonal, disponível em 26 doentes, confirmou deficiência em 92% deles, com mais de dois eixos acometidos em 50% dos casos. A mediana do volume dos tumores foi de 11,6 cm3, do maior diâmetro de 3,8cm e da soma dos três diâmetros de 8,6cm, observou estreita correlação significativa estatisticamente entre as três medidas. Quarenta porcento dos tumores eram gigantes (diâmetro maior ou igual a 4 cm). Consistência amolecida e invasão tumoral foram observadas em 87% e 67% dos tumores, respectivamente. Todos doentes foram operados pela via transesfenoidal, exceto um operado por craniotomia pterional. Complicações cirúrgicas ocorreram em cinco pacientes, três com fistula liquórica, dois com meningite e dois óbitos. A análise histológica confirmou o diagnóstico de adenoma hipofisário em todos os casos. A IHQ foi negativa para todos hormônios em 18 e positiva em 12 tumores (TSH, FSH, LH, GH ou ACTH). A IHQ para proteína P-53 foi negativa em todos os casos. A IHQ para KI-67 revelou ausência da proteína em 11, positividade em menos de 3% das células em 15 e em mais de 3% em 4 tumores. A IHQ para Bcl-2 foi positiva em apenas três pacientes. A análise molecular dos genes Bcl-2, Bax e Caspase-3 revelou expressão muito inferior nos tumores em relação à observada para um pool de hipófise normal. Observou-se correlação positiva estatisticamente significante entre os três genes porém não foi observada correlação entre os níveis destes três genes e nenhum fator de prognóstico tumoral estudado, quais sejam, idade, positividade para hormônios na IHQ, tamanho ou invasão tumoral
Pituitary adenomas are benign, slow-growing tumors that arise in the sella turcica and account for 10% to 15% of all intracranial tumors. Non-functioning pituitary adenomas (NFPA) account for around one third of all pituitary adenomas. NFPA do not clinically present as hormonal syndromes and are generally diagnosed as macroadenomas due to marked neurological and ophthalmologic symptoms and invasion of surrounding structures, beside hypopituitarism. Surgery is the gold standard to treat these tumors. It effectively relieves compressive symptoms but cure is uncommon. Despite benign in nature, NFPA usually show aggressive behavior. There are no hormonal markers and the follow-up usually is made only by magnetic resonance imaging. Apoptosis-related genes, Bcl-2, Bax, and caspase-3, were here studied in NFPA to assess their role as potential markers of tumor behavior. Out of 119 patients with pituitary adenomas treated by surgery, 30 patients (17 men, 13 women, median age 54.5 years old) harboring NFPA who underwent surgery in the Department of Functional Neurosurgery at Hospital das Clínicas Psychiatric Institute, University of S. Paulo Medical School, from August 2008 to July 2009, were studied. Information on gender, age, pituitary function, symptoms and their length was collected. Tumor dimensions were measured using magnetic resonance imaging of the sella turcica. The tumor volume was calculated by the following equation: anterior-posterior diameter x cranial-caudal diameter x lateral-lateral diameter x 0.5. Intra-operative information such as tumor invasion and consistence was recorded. Histological examination by hematoxylin-eosin staining and immunohistochemistry analysis of pituitary hormones, Ki-67, p53, and Bcl-2 were performed. The molecular analysis of Bcl-2, Bax, and caspase-3 genes was performed by real-time polymerase chain reaction (RT-PCR) in all tumor specimens collected during surgery and compared to a poll of normal pituitary gland. All patients had macroadenomas diagnosed due to visual loss (87%), headache (53%) and other neurological symptoms (17%) and one case was incidentally found. Hormonal deficits were seen in 92% of 26 cases; more than two axes were involved in half of these patients. There was found good correlation between tumor volume, largest diameter and the sum of the 3 diameters, and tumor volume was used to assess the correlations with other parameters. The median volume was 11.6 cm3. Giant tumors (4 cm) were diagnosed in 40% of the patients. Soft tumors and tumor invasion were observed in 87% and 67% of cases, respectively. A transsphenoidal approach was used in all patients, except one who had pterional craniotomy. Five patients presented post-operative complications: three had CSF leakage, two meningitis and two died. The histological examination confirmed pituitary adenoma in all cases, 18 of them were null cell and 12 showed a positive immunohistochemistry analysis for one or more hormones, mainly TSH. Immunohistochemistry analysis results for p-53 was negative in all cases; for Ki-67 was negative in 11, positive in less than 3% of the cells in 15 and positive in more than 3% of the cells in 4 cases; and for Bcl-2 was positive only in three patients. Bcl-2, Bax and caspase-3 molecular analysis revealed very low expression compared to normal pituitary values. There was found a positive correlation between these three genes but no correlation between them and age, tumor volume or invasion. The Bcl-2, Bax, and caspase-3 gene analysis by RT-PCR in NFPA did not evidence their potential as markers of tumor behavior
PDF
