RESUMO
Pituitary adenohypophyseal tumors are considered as benign and termed "adenomas". However, many tumors are invasive and a proportion of these exhibit an "aggressive behavior" with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed "carcinomas". Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.
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Carcinoma , Gradação de Tumores , Invasividade Neoplásica , Neoplasias Hipofisárias , Terminologia como Assunto , Carcinoma/classificação , Carcinoma/diagnóstico , Carcinoma/metabolismo , Carcinoma/patologia , Humanos , Invasividade Neoplásica/diagnóstico , Invasividade Neoplásica/patologia , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologiaRESUMO
The behaviour of lactotroph tumours varies between benign tumours, those cured by treatment, and that of aggressive tumours, and carcinomas with metastasis. Identification of clinical, pathological and molecular factors is essential for the early identification of patients that may have such aggressive tumours. Plasma prolactin levels and tumour size and invasion, per se, are not prognostic factors. However, tumours appearing at a young age (<20 years), especially in boys, and the presence of genetic predisposition have a poorer prognosis. In addition, lactotroph tumours in men differ from those in women, being larger, more often invasive, and resistant to dopamine agonists. They are also more often high-grade with a high risk of recurrence and malignancy. The expression of estrogen receptor α is lower than in women and is closely correlated to aggressiveness. Proliferation markers (Ki-67 expression: ≥3%, mitotic count n > 2) are correlated to invasion and proliferation, but, taken alone, their prognostic value is debatable. Based on a 5-tiered clinicopathological classification, and taking into account invasion and proliferation, a grade 2b (aggressive) lactotroph tumour has a 20× risk of progression compared to a grade 1a (benign) tumour. Moreover, lactotroph tumours are the second-most frequent aggressive and malignant tumour. Other factors, such as the expression of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]), the genes regulating invasion, differentiation and proliferation, adhesion molecules (E-cadherin), matrix metalloproteinase 9, and chromosome abnormalities (chromosomes 11, 19, and 1), have also been correlated with aggressiveness. Currently, clinical signs, a prognostic classification, and molecular and genetic markers may all help the clinician in the early identification of aggressive lactotroph tumours and enable stratification of their management.
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Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Prolactinoma/genética , Prolactinoma/patologia , Feminino , Humanos , MasculinoRESUMO
The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.
Assuntos
Tumores Neuroendócrinos/classificação , Humanos , Agências Internacionais , Organização Mundial da SaúdeAssuntos
Adenoma , Tumores Neuroendócrinos , Doenças da Hipófise , Neoplasias Hipofisárias , Humanos , HipófiseRESUMO
Twenty-one human fetal brains from 13 to 28 gestational weeks were studied macroscopically to describe the morphological stages of sulcal and gyral development in the sensorimotor cortex. In particular, the morphological appearance of the pericentral lateral cortex (sensorimotor cortex) and opercula was noted, as well as the vascularization of these regions. The central cerebral sulci were the first macroscopical structures to be identified on the lateral surface of the human cerebral hemisphere. Four chronological stages of sensorimotor cortex development were defined: stage 1: appearance at 18-19 gestational weeks (GWs) of the inferior part of the central cerebral sulcus; stage 2: development of the pericentral lateral regions and the beginning of opercularization at 20-22 GWs; stage 3: development of parietal and temporal cortices and the covering of the postcentral insular region at 24-26 GWs; and finally stage 4: maturation of the central cerebral regions at 27-28 GWs. These observations indicate the concomitance in the initiation of maturation of the pericentral cerebral cortices.
Assuntos
Desenvolvimento Fetal , Córtex Sensório-Motor/anatomia & histologia , Cadáver , Feminino , Feto/anatomia & histologia , Humanos , Masculino , Córtex Sensório-Motor/irrigação sanguíneaRESUMO
Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.
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Hipófise/patologia , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hipófise/ultraestrutura , Neoplasias Hipofisárias/cirurgia , Prognóstico , Recidiva , Estudos Retrospectivos , Sensibilidade e Especificidade , Fatores Sexuais , Adulto JovemRESUMO
Temozolomide (TMZ) has been proposed as a therapeutic option in aggressive pituitary tumors. Among the published cases, GH expressing tumors were rare. We describe a patient with initially benign silent GH adenoma that transformed into an aggressive GH secreting tumor resistant to usual therapy. MGMT expression was high and the MGMT promoter was unmethylated. Before this aggressive course, patient received three cycles of TMZ; no response was observed. Four cases of GH aggressive tumor treated by TMZ have been reported. Response to TMZ was observed in one of these four patients. Predictive factors of failure of TMZ remain unclear.
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Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/análogos & derivados , Hormônio do Crescimento Humano/metabolismo , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Metilases de Modificação do DNA/análise , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/análise , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Antígeno Ki-67/análise , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Temozolomida , Proteína Supressora de Tumor p53/análise , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/genéticaRESUMO
According to the World Health Organization classification of pituitary tumors, only tumors with systemic metastasis must be considered as carcinomas. Invasive tumors with multiple recurrences are only classified as aggressive tumors or "atypical adenomas". To illustrate the problems encountered in the pathological diagnosis of pituitary carcinoma and in patient management, we present two male patients operated on for an aggressive prolactin pituitary adenoma with and without metastasis. In case 1, 5 surgeries, 3 irradiations, increased doses of dopamine agonists, and trials of temozolomide and carboplatine-VP16 failed to control tumor progression and the appearance of metastases which lead to death 16 years after onset. In case 2, based on the initial diagnosis of an aggressive-invasive adenoma that was resistant to dopamine agonists, gamma-Knife irradiation was initially performed on the intra-cavernous remnant. Eight years after onset, the remnant remained stabilized and the plasma PRL normalized under dopamine agonist. From these 2 cases alongside other cases found in the literature, we propose that the association of certain clinical signs (male sex, dopamine-resistant hyperprolactinemia), radiological signs (invasive macro or giant tumor on MRI) and histological signs (angiogenesis, Ki-67 > 3%, p53 positive, mitoses >2 per high power field, vascular invasion, up-regulation of genes related to invasion and proliferation, and allelic loss of chromosome 11) might suggest aggressiveness and be suspicious of malignancy before the appearance of metastasis. The early detection of an aggressive phenotype of a prolactin pituitary tumor should permit the earlier establishment of the optimum therapeutic strategy associating surgery and radiotherapy to delay or inhibit metastasis.
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Neoplasias Hipofisárias/diagnóstico , Antineoplásicos/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/tratamento farmacológico , Prolactina/sangueRESUMO
Pituitary carcinomas are rare, accounting for about 0.2% of all pituitary tumours. They represent a challenge to clinical practice in both diagnosis and treatment. They may present initially as typical pituitary adenomas, with a delayed appearance of aggressive signs, or as aggressive tumours from the outset. Predicting the pituitary tumour behaviour remains difficult: increased mitotic, Ki-67 and P53 indices might be associated with tumour aggression. The treatment of pituitary carcinomas and aggressive pituitary tumours includes surgery, adjuvant medical treatment, external beam radiotherapy and chemotherapy. Until recently, the treatment of pituitary carcinomas was mainly palliative and did not seem to increase overall survival. Recent case reports have detailed the successful use of temozolomide, an orally administered alkylating agent used to treat malignant gliomas, in the management of pituitary carcinomas and aggressive pituitary tumours. The outcome of treatment might depend on the expression of O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that potentially interferes with drug efficacy. This review describes the clinical presentation and response to temozolomide in 44 patients with pituitary carcinomas or aggressive pituitary tumours reported in the literature. The results suggest that temozolomide should be considered a drug of major importance in the therapeutic algorithm of aggressive pituitary tumours and pituitary carcinomas. Because of the inconsistency of published data, MGMT expression should probably not be taken as a reason to deny these patients the potential benefit of temozolomide treatment, taking into account the paucity of other available treatments.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/análogos & derivados , Neoplasias Hipofisárias/tratamento farmacológico , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/uso terapêutico , Humanos , Neoplasias Hipofisárias/enzimologia , Temozolomida , Proteínas Supressoras de Tumor/metabolismoRESUMO
To evaluate the antitumoral efficacy of everolimus in pituitary carcinoma resistant to temozolomide, the correlation with mammalian target of rapamycin (mTOR) signaling in the tumor and to present recent advances and future treatments of pituitary carcinomas. Pituitary carcinomas are rare and largely unresponsive to current treatment options. Recent reports on the antitumoral efficacy of temozolomide in some such patients are encouraging, yet most patients appear to show resistance to its actions. As a potential alternative, the mTOR inhibitor, everolimus, has been shown to potently inhibit pituitary cell proliferation highlighting mTOR inhibition as a promising therapeutic approach for pituitary carcinomas. We described the tumoral effects of a combination therapy with everolimus (5 mg/day) and octreotide (30 mg/month) and the mTOR signalling expression in a patient with pituitary ACTH carcinoma, compared to 17 other ACTH adenomas. Clinical and biochemical evaluation were performed every month, and imaging after 3 month of treatment. mTOR signaling was assessed by microarray expression analysis of each of the 18 adenoma tissues. Combined therapy failed to control pituitary tumor growth and ACTH secretion. Slight activation of mTOR signaling was found in all ACTH tumors alongside important variations between tumors. Low antitumor efficacy shown by everolimus might be explained by the weak activation of mTOR pathway in ACTH tumors. Everolimus treatment was inefficient at controlling secretion and tumor growth of one ACTH pituitary carcinoma. More clinical cases, with mTOR signalling expression analysis of the tumor, must be published before any conclusions can be drawn.
Assuntos
Dacarbazina/análogos & derivados , Neoplasias Hipofisárias/tratamento farmacológico , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Everolimo , Humanos , Masculino , Pessoa de Meia-Idade , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , TemozolomidaRESUMO
Objective: To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC). Design: Electronic survey August 2020-May 2021. Results: 96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8-12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis. Conclusion: APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.
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Adenoma , Carcinoma , Neoplasias Hipofisárias , Adenoma/patologia , Hormônio Adrenocorticotrópico/metabolismo , Bevacizumab/uso terapêutico , Carcinoma/tratamento farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno Ki-67/metabolismo , Masculino , Neoplasias Hipofisárias/patologia , Radioisótopos/uso terapêutico , Receptores de Peptídeos/metabolismo , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismoRESUMO
OBJECT: Because of their size and lateral extension, total removal of nonfunctioning pituitary adenomas (NFPAs) remains a challenge and postoperative tumor remnants are frequent. Endoscopy has improved the surgeon's view; however, its superiority in terms of surgical outcome remains undetermined. The authors' aim in this study was to compare the clinical results and morbidity between microscopic and endoscopic techniques in 164 patients with NFPAs. METHODS: Tumoral (3D MR imaging), endocrinological, and ophthalmological results and morbidity were compared between 2 groups of 82 patients with newly diagnosed NFPAs surgically treated via either a sublabial microscopic approach (Group B) or a fully endonasal endoscopic technique (Group A). RESULTS: The groups showed no difference in terms of clinical features, tumor size, or cavernous sinus invasion (p > 0.05). One year postoperatively, the quality of resection was significantly improved in Group A (gross-total removal [GTR]: 74% vs 50% in Group B, p = 0.002) with greater control of lateral extension (Knosp Grade 2: GTR 88.2% vs 47.8% in Group B, p = 0.02; Knosp Grade 3: 67.9% vs 16.7% in Group B, p < 0.001) and suprasellar extension (tumor height 20-30 mm: GTR 76% vs 53% in Group B, p = 0.01). Endocrinological outcome in patients with a partial deficiency in anterior pituitary function preoperatively was significantly better in Group A (improvement 56% vs 25% in Group B, stabilization 22% vs 46%, and aggravation 22% vs 29%; p = 0.01). Among the ophthalmologically symptomatic patients, 100% from Group A improved compared with 93% in Group B (p = 0.35). Lastly, no significant difference was found regarding morbidity. These data were supported by the literature in which the GTR rate is consistently higher for endoscopy compared with microscopy. CONCLUSIONS: In this large series of patients with NFPAs, endoscopy improved the quality of resection and endocrinological outcome. Larger studies focusing on the impact of these promising results on the long-term recurrence of NFPAs are warranted.
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Adenoma/cirurgia , Endoscopia/métodos , Procedimentos Neurocirúrgicos/métodos , Neoplasias Hipofisárias/cirurgia , Resultado do Tratamento , Adenoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento Tridimensional/métodos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Microscopia/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Oftalmologia , Hormônios Hipofisários/metabolismo , Neoplasias Hipofisárias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Estudos Retrospectivos , Estatísticas não Paramétricas , Adulto JovemRESUMO
Although usually benign, anterior pituitary tumours occasionally exhibit aggressive behaviour, with invasion of surrounding tissues, rapid growth, resistance to conventional treatments and multiple recurrences. In very rare cases, they metastasize and are termed pituitary carcinomas. The time between a 'classical' pituitary tumour and a pituitary carcinoma can be years, which means that monitoring should be performed regularly in patients with clinical (invasion and/or tumour growth) or pathological (Ki67 index, mitotic count and/or p53 detection) markers suggesting aggressiveness. However, although both invasion and proliferation have prognostic value, such parameters cannot predict outcome or malignancy without metastasis. Future research should focus on the biology of both tumour cells and their microenvironment, hopefully with improved therapeutic outcomes. Currently, the initial therapeutic approach for aggressive pituitary tumours is generally to repeat surgery or radiotherapy in expert centres. Standard medical treatments usually have no effect on tumour progression but they can be maintained on a long-term basis to, at least partly, control hypersecretion. In cases where standard treatments prove ineffective, temozolomide, the sole formally recommended treatment, is effective in only one-third of patients. Personalized use of emerging therapies, including peptide receptor radionuclide therapy, angiogenesis-targeted therapy and immunotherapy, will hopefully improve the outcomes of patients with this severe condition.
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Craniofaringioma/patologia , Neoplasias Hipofisárias/patologia , Craniofaringioma/terapia , Humanos , Imunoterapia , Neoplasias Hipofisárias/terapia , Temozolomida/uso terapêutico , Microambiente TumoralRESUMO
SUMMARY: A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare. LEARNING POINTS: It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1). Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis. Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.
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Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, "aggressive" and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) or gonadotroph (SF1 lineage), null cell or immunonegative tumor and plurihormonal tumors. The WHO 2017 classification suggested that subtypes, such as male lactotroph, silent corticotroph and Crooke cell, sparsely granulated somatotroph, and silent plurihormonal PIT1 positive tumors, should be considered as "high risk" tumors. However, the prognostic impact of these subtypes and of each morphologic type remains controversial. In contrast, the French five-tiered classification, taking into account the invasion, the immuno-histochemical (IHC) type, and the proliferative markers (Ki-67 index, mitotic count, p53 positivity), has a prognostic value validated by statistical analysis in 4 independent cohorts. A standardized report for the diagnosis of pituitary tumors, integrating all these parameters, has been proposed by the European Pituitary Pathology Group (EPPG). In 2020, the pituitary pathologist must be considered as a member of the multidisciplinary pituitary team. The pathological diagnosis may help the clinician to adapt the post-operative management, including appropriate follow-up and early recognition and treatment of potentially aggressive forms.
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Acromegaly is mainly due to the somatotroph pituitary neuroendocrine tumors (PitNET)s. These have been subtyped into densely granulated (DG) and sparsely granulated (SG) tumors, which differ in clinical, histological and biological characteristics and in response to somatostatin analogs (SA)s. The variable remission rate after surgical resection, as first line treatment, has increased interest in identifying pathological markers to better predict the response to medical treatment. Several techniques have shown somatotroph tumors to express somatostatin receptors (SSTR)s, and mainly SSTR2 and SSTR5. The molecular methods appear to give contradictory results, are expansive and cannot be routinely performed. Immunohistochemistry, while being the most powerful technique, requires optimal fixation and the use of monoclonal antibodies against at least SSTR2 and SSTR5. Almost all somatotroph tumors express SSTR2 or SSTR5, and, in great majority, at a high level. More importantly, the type of SSTR, the level of expression, and the response to SA treatment appear well correlated. Indeed, a significantly higher expression of SSTR2 in DG compared to in SG tumors likely explains the better response of DG tumors to the normalization of growth hormone and insulin-like growth factor-1 under SA. However, a reproducible scoring and a cut-off from which the SA efficacy can be reliably predicted, remain to be found. In conclusion, the SSTR expression profile and morphological subtypes of the somatotroph tumor may help predict the response to medical treatment. Such pathological profiling could become a useful decision-making tool for clinicians in the context of a multidisciplinary approach, after surgery failure.
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Adenoma/tratamento farmacológico , Adenoma/patologia , Biomarcadores/análise , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Acromegalia/tratamento farmacológico , Acromegalia/patologia , Animais , Humanos , Valor Preditivo dos Testes , Prognóstico , Receptores de Somatostatina/genéticaRESUMO
TSH (thyroid-stimulating hormone)-secreting tumors are the rarest type of pituitary tumor. The objective of this study was to describe initial presentation and follow-up in patients presenting TSH-secreting tumors and to characterize the pathological features, based on a cohort of 20 patients treated in our referral center, between 1981 and 2014. Most of the patients (75%) were female, aged around 50 years (mean: 50±13 years). Initial symptoms were hyperthyroidism (8/20) and/or tumor mass-related symptoms. Median time to diagnosis was 18 months. Biochemical hyperthyroidism was found in 15 patients. Most of the tumors were macroadenomas (75%) and 30% were invasive. Seventeen patients underwent transsphenoidal surgery. All tumors expressed TSH, with>50% positive cells. Eleven were monohormonal and 6 plurihormonal, expressing ßTSH plus growth hormone (GH) and/or prolactin (PRL). Both subtypes showed high expression of Pit-1 and SSTR2A somatostatin receptors. SSTR5 was slightly expressed in the plurihormonal subtype. Ki-67 index was elevated (≥3%) in only one tumor. Signs of hyperthyroidism were more frequent in the plurihormonal than in the monohormonal subtype. At final follow-up (median: 34.79±66.7 months), 75% of the patients were in complete remission after surgery; persistent hyperthyroidism was controlled by somatostatin analogs, alone (n=3) or associated to radiotherapy (n=1). The multidisciplinary approach promoted early diagnosis and control of hyperthyroidism by neurosurgical treatment, associated to somatostatin analogs or not. Clinical/pathological correlations highlighted the variations in immune profiles and in clinical and biological symptoms.
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Adenoma , Neoplasias Hipofisárias , Tireotropina/metabolismo , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Adenoma/terapia , Adulto , Idoso , Feminino , França , História do Século XX , História do Século XXI , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/patologia , Hipertireoidismo/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/terapia , Estudos Retrospectivos , Somatostatina/análogos & derivados , Somatostatina/uso terapêuticoRESUMO
Background: Thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) can be present in chronic autoimmune thyroiditis. Transplacental TRAb transfer can lead to fetal thyroid dysfunction and serious complications. Patient Findings: We report the case of a woman with autoimmune hypothyroidism and extremely high TRAb levels, with blocking and stimulating activities (biological activities characterized with Chinese hamster ovary cells expressing TSHR). At week 22 of her first pregnancy, sonography detected fetal growth retardation and cardiac abnormalities (extreme tachycardia, right ventricular dilatation, pericardial effusion). The mother's TRAb level, assayed later, was 4030 IU/L (n < 10). Delivered via caesarean section gestational week 30, the newborn girl had several malformations, signs of malnutrition, goiter and hyperthyroidism associated with elevated TRAb (1200 IU/L). The newborn died 26 days after delivery. Faced with persistently high TRAb levels and a desire to become pregnant again, the woman was treated with three consecutive 740-MBq activities of iodine-131, which resulted in a decrease in TRAb to 640 IU/L. The patient had two subsequent pregnancies 16 and 72 months after the radioiodine administration. During the close follow-ups, fetal development was normal, and initial TRAb levels during the two pregnancies were 680 and 260 IU/L, respectively, which initially decreased but then increased in late pregnancy. In both cases, labor was induced at 34 weeks. The newborns, mildly hyperthyroid at birth, required carbimazole treatment at days 5 and 2, respectively. The mild hyperthyroidism despite high TRAb levels was likely due to the concomitant presence of stimulating and blocking TRAb. The two girls, now aged 12 and 8 years, are in good health. The mother has no detectable thyroid gland tissue and is euthyroid on levothyroxine (175 µg/d). Her TRAb level gradually decreased to 136 IU/L. Summary and Conclusions: This remarkable case illustrates the severe consequences of untreated fetal hyperthyroidism and the need to assay and follow-up TRAb levels in women of reproductive age with autoimmune thyroiditis.
Assuntos
Autoanticorpos/sangue , Doença de Hashimoto/imunologia , Complicações na Gravidez/imunologia , Receptores da Tireotropina/imunologia , Tireoidite Autoimune/imunologia , Adulto , Criança , Doença Crônica , Feminino , Doença de Hashimoto/complicações , Humanos , Recém-Nascido , Gravidez , Tireoidite Autoimune/complicaçõesRESUMO
Patients affected by the multiple endocrine neoplasia type I syndrome (MEN1) display a high incidence of pituitary adenomas, though it is still unknown whether these pituitary tumors have specific pathologic features that would distinguish them from sporadic pituitary adenomas. Pituitary tissue specimens of 77 MEN1 patients from the GTE (Groupe d'étude des Tumeurs Endocrines) register were compared with unselected 2509 non-MEN1 sporadic pituitary tumors and also to a control subgroup of 296 cases, where 1 MEN1 tumor was matched with 4 sporadic tumors of the same hormonal immunoprofile. Sex, age, size, and invasiveness of tumors, and menin gene mutations were documented. Histologic analysis took into account 33 items, including immunocytochemical data, the proliferative marker Ki-67, and an examination of the juxtatumoral pituitary. MEN1 tumors were significantly larger and more often invasive by histology. MEN1 patients with large pituitary tumors (grade IV) were younger than non-MEN1 patients. MEN1 tumors had no other characteristic histologic features and no predominance of any one hormone producing subtype. However, plurihormonal adenomas versus monohormonal and nonimmunoreactive adenomas were more frequent in MEN1 tumors (39%) than in the control non-MEN1 group (P = 0.001). Especially, the growth hormone and prolactin plurihormonality with unusual association with follicle-stimulating hormone, luteinizing hormone, or adrenocorticotropic hormone was more frequent in MEN1 tumors. In addition, multiple adenomas were significantly more frequent (4% vs. 0.1%; P < 0.0001), especially prolactin-adrenocorticotropic hormone. Somatotroph hyperplasia, with or without a microadenoma was found in only 3 MEN1 patients, with growth hormone-releasing hormone hypersecretion by a pancreatic tumor in 2 of them. All types of mutation were observed, including frameshifts, nonsenses, missenses, and 1 case of germline MEN1 encompassing large deletion, strongly suggesting the absence of any phenotype-genotype correlation.
Assuntos
Adenoma/patologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Hipófise/patologia , Neoplasias Hipofisárias/patologia , Adenoma/química , Adenoma/genética , Adolescente , Hormônio Adrenocorticotrópico/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proliferação de Células , Feminino , Hormônio Foliculoestimulante/análise , Regulação Neoplásica da Expressão Gênica , Hormônio do Crescimento Humano/análise , Humanos , Hiperplasia , Imuno-Histoquímica , Antígeno Ki-67/análise , Hormônio Luteinizante/análise , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/química , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Invasividade Neoplásica , Estadiamento de Neoplasias , Hipófise/química , Neoplasias Hipofisárias/química , Neoplasias Hipofisárias/genética , Prolactina/análise , Proteínas Proto-Oncogênicas/genética , Tireotropina/análiseRESUMO
BACKGROUND: Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas. METHODS: We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36-58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline. SELECTED RECOMMENDATION: (i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.