Nádory hypofýzy jsou běžné intrakraniální tumory dospělé populace. Naprostá většina nádorů hypofýzy je představována pituitárními neuroendokrinními tumory (PitNETy, dříve adenomy), které lze klasifikovat v závislosti na linii diferenciace nádorových buněk, jež odráží buněčné populace normální hypofýzy. Příslušnost k různým subpopulacím je řízena jedním či více transkripčními faktory (Pit1, Tpit, SF1 a GATA3), které regulují mimo jiné též hormonální produkci v normálních i nádorových buňkách hypofýzy. Tento přehledový článek v krátkosti z perspektivy diagnostické patologie shrnuje novinky ve WHO klasifikaci PitNETů a dále se zabývá vzácnějšími lézemi hypofýzy, jmenovitě kraniofaryngiomy, pituicytomy a sekundárními nádory sellární oblasti.
Pituitary tumors are common intracranial tumors in adults. Pituitary neuroendocrine tumors (PitNETs, formerly adenomas) represent a vast majority of pituitary lesions. These tumors can be classified according to the lineage of differentiation in tumor cells that corresponds to cellular subpopulations of normal pituitary. These cell lineages are determined by one or more transcription factors (Pit1, Tpit, SF1 and GATA3) that also regulate hormonal production in both normal pituitary cells and their neoplastic counterparts. This review article summarizes briefly current approach in histopathological diagnosis of PitNETs according to the latest WHO classification. Furthermore, rarer entities, including pituictyomas and craniopharyngiomas are discussed, as well as secondary tumors of sellar region.
- MeSH
- histologické techniky MeSH
- kraniofaryngeom diagnóza patologie MeSH
- lidé MeSH
- nádory hypofýzy * diagnóza patologie MeSH
- neuroendokrinní nádory MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.
Článek se zabývá problematikou personalizované léčby akromegalie s důrazem na predikci terapeutické odpovědi. V kontextu rychle se rozvíjející oblasti personalizované medicíny zdůrazňuje variabilitu klinických, biochemických a radiologických rysů akromegalie a potřebu přesnější klasifikace a personalizovaných terapeutických přístupů. Chirurgie zůstává hlavním terapeutickým přístupem a v článku jsou analyzovány předoperační prediktory úspěšné operace, jako jsou vyšší koncentrace růstového hormonu před zákrokem a negativní vliv invaze kavernózního sinu. Při terapii somatostatinovými analogy jsou zkoumány faktory, včetně intenzity signálu na MRI a exprese receptorů SSTR2A a SSTR5. Dále je diskutován význam matematických analýz a modelů umělé inteligence při předpovědi terapeutické odpovědi. V současné době je nezbytné vyvinout nové algoritmy pro výběr terapie, aby bylo možné léčit pacienty s akromegalií efektivněji.
The article deals with the issue of personalized treatment of acromegaly with emphasis on prediction of therapeutic response. In the context of the rapidly developing field of personalized medicine, it emphasizes the variability of the clinical, biochemical and radiological features of acromegaly and the need for more accurate classification and personalized therapeutic approaches. Surgery remains the main therapeutic approach, and this article analyzes preoperative predictors of successful surgery, such as higher growth hormone concentrations before surgery and the negative impact of cavernous sinus invasion. Factors including signal intensity on MRI and SSTR2A and SSTR5 receptor expression are investigated during somatostatin analogue therapy. The importance of mathematical analyses and artificial intelligence models in predicting therapeutic response is also discussed. Currently, it is necessary to develop new algorithms for therapy selection in order to treat patients with acromegaly more effectively.
- MeSH
- akromegalie * terapie MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- neurochirurgické výkony MeSH
- somatostatin analogy a deriváty farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Pasireotid je analog somatostatinu 2. generace s vazbou na více podtypů somatostatinových receptorů, zejména typu 5 a 2. To zvyšuje jeho účinnost v terapii akromegalických a kortikotropních adenomů hypofýzy. Zároveň je ale vysvětlením pro významný nežádoucí účinek – potlačení sekrece inzulinu s rozvojem poruchy glukózové tolerance nebo diabetu. U akromegalie je pasireotid lékem druhé volby, po selhání analog 1. generace. Jeho účinnost byla prokázána ve studii přímo srovnávající oktreotid s pasireotidem u dosud neléčených nemocných a ve studiích PAOLA a PAPE. Volíme jej u pacientů s větším reziduem majícím tendenci k růstu, při vyšší proliferační aktivitě nádoru a v přítomnosti somatostatinových receptorů typu 5 ve vysoké hustotě. Kombinovaná terapie s pegvisomantem vedla k možnosti snížit dávku tohoto antagonisty růstového hormonu. Hyperglykemie je reverzibilní po vysazení léku a lze ji dobře zvládnout inhibitory DPP-4, agonisty GLP-1 nebo inzulinem.
Pasireotide is a second-generation somatostatin analogue that binds more subtypes of somatostatin receptors, especially type 5 and 2. This increases its effectiveness in the treatment of acromegalic and corticotroph pitNETs. On the other hand, it explains the prominent adverse event – suppression of insulin secretion and development of impaired glucose tolerance and diabetes. In acromegaly, pasireotide is the drug of second choice after the failure of first-generation somatostatin analogues. Its effectiveness was confirmed in a head-tohead study with octreotide and in studies PAOLA and PAPE. It is used in patients with a larger residuum of petNET after surgery, especially with a tendency to grow, in higher proliferative activity of tumour and presence of SSTR-5 in high density. Combined therapy with pegvisomant enabled to decrease the dose of this growth hormone receptor antagonist considerably. Hyperglycaemia is reversible after discontinuation of the drug and can be well managed with DPP-4 antagonists, GLP-1 agonists or insulin.
- Klíčová slova
- pasireotid,
- MeSH
- akromegalie * farmakoterapie MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- somatostatin farmakokinetika farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
Cauda equina neuroendocrine tumors (CENETs) are neoplasms of uncertain histogenesis with overlapping features between those of paragangliomas (PGs) and visceral neuroendocrine tumors (NETs). We have explored their biological relationship to both subsets of neuroendocrine neoplasms. The clinical and radiological features of a cohort of 23 CENETs were analyzed. A total of 21 cases were included in tissue microarrays, along with a control group of 38 PGs and 83 NETs. An extensive panel of antibodies was used to assess epithelial phenotype (cytokeratins, E-cadherin, EpCAM, Claudin-4, EMA, CD138), neuronal and neuroendocrine features (synaptophysin, chromogranin A, INSM1, neurofilaments, NeuN, internexin-α, calretinin), chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase), and possible histogenesis (Sox2, T-brachyury, Oct3/4, Sox10). The cohort included 5 women (22%) and 18 men (78%). The average age at the time of surgery was 48.3 years (range from 21 to 80 years). The average diameter of the tumors was 39.27 mm, and invasion of surrounding structures was observed in 6/21 (29%) tumors. Follow-up was available in 16 patients (median 46.5 months). One tumor recurred after 19 months. No metastatic behavior and no endocrine activity were observed. Compared to control groups, CENETs lacked expression of epithelial adhesion molecules (EpCAM, CD138, E-cadherin, Claudin-4), and at the same time, they lacked features of chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase). We observed no loss of SDHB. Cytokeratin expression was present in all CENETs. All the CENETs showed variable cytoplasmic expression of T-brachyury and limited nuclear expression of Sox2. These findings support the unique nature of the neoplasm with respect to NETs and PGs.
- MeSH
- adhezní molekula epiteliálních buněk MeSH
- cauda equina * metabolismus patologie chirurgie MeSH
- claudin-4 MeSH
- lidé MeSH
- lokální recidiva nádoru patologie MeSH
- nádory centrálního nervového systému * patologie MeSH
- neuroendokrinní nádory * patologie MeSH
- paragangliom * MeSH
- represorové proteiny MeSH
- transkripční faktory MeSH
- tyrosin-3-monooxygenasa MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Subklinická hypotyreóza je poměrně častým jevem, zejména u starších pacientů. Je definována zvýšeným TSH spolu s normálními hladinami volných hormonů štítné žlázy. Oproti klinicky vyjádřené hypotyreóze jsou její rizika podstatně menší, a proto je klíčové vybrat pacienty, u kterých potencionální benefit léčby převáží její nežádoucí účinky. K tomu je třeba vzít v potaz věk pacienta, komorbidity, příznaky a míru elevace TSH. Léčba spočívá v substituci levothyroxinem s šetrnou titrací dávky vedoucí k normalizaci TSH. Neléčení pacienti by měli být sledováni v závislosti na rizikových faktorech, zejména pak na riziku progrese do klinicky vyjádřené hypotyreózy. Přístup ke každému pacientovi by měl být vždy individuální a flexibilní.
Subclinical hypothyroidism is a relatively common condition characterized by elevated serum TSH levels, but normal free thyroxine levels. The risks associated with subclinical hypothyroidism are less severe compared to those with overt hypothyroidism, making it essential to carefully select patients who would benefit from the treatment. Factors such as the patient ́s age, comorbidities, symptoms, and TSH concentration need to be considered in this selections proces. The therapy, if required, consists of levothyroxine substitution with carefull dose titration to avoid overtreatment. The goal is to normalize TSH levels. Untreated patients should be folowed up accordingly to their risk factors mainly the risk of progression to overt hypothyroidism. Aproach to each patient should be individulized and flexible.
- MeSH
- hormony štítné žlázy krev MeSH
- hypotyreóza * diagnóza farmakoterapie komplikace MeSH
- lidé MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- testy funkce štítné žlázy MeSH
- thyreotropin krev MeSH
- thyroxin aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
HoxB13 is a transcription factor involved in defining of posterior endodermal derivatives, including prostate and rectum. While it is used as a marker of prostatic adenocarcinoma, it has not been studied systematically in neuroendocrine neoplasms. Thus, we performed HoxB13 immunohistochemistry in tissue microarrays and the whole sections of 232 neuroendocrine neoplasms. These included 34 paragangliomas (PGs), 20 cauda equina neuroendocrine tumors (CENETs), 123 well-differentiated neuroendocrine tumors (WDNETs), and 55 neuroendocrine carcinomas (NECs). WDNETs were additionally analyzed with SATB2, and colorectal WDNETs with CDX2 and serotonin immunohistochemistry. In total, HoxB13 immunoreactivity was observed in 95% (19/20) CENETs, 10.6% (13/123) WDNETs, and 12.9% (7/54) NECs. No PGs were positive. Large intestine WDNETs expressed HoxB13 in 68.4% (13/19); five negative tumors originated in cecum and one in rectum. In rectum, 92.9% (13/14) WDNETs expressed HoxB13. HoxB13 was 92.9% sensitive and 100% specific, showing 100% positive predictive value for the rectal origin of WDNET. In NECs, HoxB13 was positive in 15.4% (2/13) GIT tumors and 80% (4/5) prostatic NECs, but in none of urinary bladder NECs (0/8). SATB2 was positive in 17.1% (21/123) WDNETs, including 78.9% (15/19) of colorectal WDNETs, 71.4% (5/7) appendiceal WDNETs, and 2.9% (1/34) small intestine WDNETs. All 4 SATB2-negative large bowel tumors originated in the cecum. When both markers combined, HoxB13+/SATB2+ immunoprofile was seen exclusively in rectal WDNETs (positive predictive value 100%), while HoxB13-/SATB2+ immunoprofile was highly suggestive of the appendiceal origin (positive predictive value 71.4%). Therefore, HoxB13 can be useful as an immunohistochemical marker of rectal WDNETs and prostatic NECs.
- MeSH
- homeodoménové proteiny MeSH
- kolorektální nádory * MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- nádory močového měchýře * MeSH
- nádory rekta * diagnóza patologie MeSH
- neuroendokrinní karcinom * diagnóza MeSH
- neuroendokrinní nádory * diagnóza patologie MeSH
- transkripční faktory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Solitary fibrous tumors (SFTs) may show unusual morphologies, and in such circumstances, an unexpected immunoprofile can be misleading. Following an index case of myxoid meningeal SFT with a neuroendocrine immunoprofile, we decided to assess a neuroendocrine profile in SFTs from various locations. The cohort of 9 meningeal and 28 extrameningeal SFTs was evaluated for CNS WHO grade (G1-G3) and 4-tiered Demicco risk stratification. Immunohistochemical detection of synaptophysin, chromogranin, INSM1, CD56, and CD57 was performed in each case and semiquantitatively assessed (0: no expression; 1+: <10% positive; 2+: 11-50%; and 3+: >51%); whole sections (meningeal SFTs) or tissue microarray (extrameningeal SFTs) were used for immunohistochemistry. The cohort included 13 men and 24 women. Meningeal SFTs included 5 WHO G1, 3 WHO G2, and 1 WHO G3 tumors. Extrameningeal SFTs included 21 low-risk, 4 intermediate-risk, and 2 high-risk tumors. INSM1 immunoreactivity was observed in 12 of 37 cases (32%; 8 cases 1+, 3 cases 2+, and 1 case 3+); synaptophysin was positive in 6 of 35 cases (19%; 5 cases 1+ and 1 case 2+); CD56 was positive in 20 of 37 cases (54%; 16 cases 1+, 3 cases 2+, and 1 case 3+); and CD57 was expressed in 14 of 36 cases (39%; 5 cases 1+, 4 cases 2+, and 5 cases 3+). Chromogranin positivity was not observed. No significant association was observed between expression of neuroendocrine markers and tumor grade, Demicco risk group or meningeal and extrameningeal location. Extrapleural SFTs showed a tendency for positivity of INSM1 (P = .014, χ2) and CD57 (P = .017, χ2) compared to pleural SFTs.
- MeSH
- chromograniny MeSH
- lidé MeSH
- meningeální nádory * diagnóza patologie MeSH
- nádorové biomarkery metabolismus MeSH
- nádory měkkých tkání * MeSH
- neuroendokrinní nádory * MeSH
- represorové proteiny metabolismus MeSH
- solitární fibrózní tumory * diagnóza patologie MeSH
- synaptofysin metabolismus MeSH
- těžká forma horečky s trombocytopenickým syndromem * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Terapie levothyroxinem je součástí léčby diferencovaného karcinomu štítné žlázy již po desetiletí. Levothyroxin je podáván pacientům po totální tyreoidektomii (s nebo bez následné aplikace radiojodu) nejen k navození eutyreózy, ale také k potlačení produkce thyreotropního hormonu (TSH), protože TSH je považován za růstový faktor pro folikulární buňky štítné žlázy. Hlavní nevýhodou této léčby jsou známá rizika spojená s iatrogenně navozenou subklinickou či až klinickou hypertyreózou. Proto je nezbytný individuální přístup s porovnáním rizika rekurence onemocnění a rizika nežádoucích účinků supresní terapie v korelaci s komorbiditami a celkovým stavem pacienta. Časté a důsledné sledování pacientů s adekvátní úpravou dávky levothyroxinu k udržení TSH v cílovém rozmezí dle doporučení Americké tyroidální asociace (ATA) je zcela klíčové.
Levothyroxine therapy in management of diferentiated thyroid carcinoma (DTC) has been common practice for decades. Levothyroxine is being administered to patiens with DTC after total thyreoidectomy (with or without postopreative radioiodine treatment) not only to restore euthyroidism but to suppress the production of thyroid-stimulating hormone (TSH) as well because TSH is considered as a growth factor for thyroid follicular cells. However there has been a downside to this threatment recently. The main concerns are the known risks related to iatrogenic subclinical or even mild but clinicaly overt iatrogenic hyperthyroidism. Therefore individualized treatment approach aiming to balance between the risk of tumor recurence and the risks related to hypertyhroidism in view of pateints age, risk factors and comorbidities is essential. Close folow-up is therefore necessary with frequent dose adjustments according to target TSH values published in American Thyroid Association guidelines.
- MeSH
- hormonální substituční terapie MeSH
- karcinom chirurgie farmakoterapie MeSH
- lidé MeSH
- nádory štítné žlázy * chirurgie farmakoterapie MeSH
- nežádoucí účinky léčiv MeSH
- rizikové faktory MeSH
- thyreotropin účinky léků MeSH
- thyroxin * aplikace a dávkování terapeutické užití MeSH
- tyreoidektomie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Phox2B is a transcription factor responsible for chromaffin cell phenotype. Although it is used routinely for diagnosis of neuroblastoma, previous reports concerning its utility in the diagnosis of neuroendocrine neoplasms have been conflicting. We assessed Phox2b immunoreactivity in different neuroendocrine neoplasms. Tissue microarrays or whole sections of 36 paragangliomas (PGs), 91 well-differentiated neuroendocrine tumours of different organs (WDNETs), 31 neuroendocrine carcinomas (NECs), and 6 olfactory neuroblastomas (ONBs) were stained with Phox2B antibody (EP312) and GATA3. The percentage of positive cells and intensity was analysed using H-score. Phox2B immunoreactivity was seen in 97.2% (35/36) PGs, 11% (10/91) WDNETs, 9.7% (3/31) NECs, and 16.7% (1/6) ONBs. PGs were significantly more often positive (p < 0.001, χ2) than other neuroendocrine tumours, showing highest H-score (mean 144.9, SD ± 75.1) and percentage of positive cells (median 81.3%, IQR 62.5-92.5%). Compared to Phox2B-positive WDNETs, PGs showed significantly higher H-score (median 145 vs 7.5, p < 0.001) and percentage of positive cells (median 82.5% vs 4.5%, p < 0.001). Phox2B positivity was 97.2% sensitive and 89% specific for the diagnosis of PG. GATA3 was 100% sensitive and 88% specific for the diagnosis of PG. When combined, any Phox2B/GATA3 coexpression was 97.1% sensitive and 99.1% specific for the diagnosis of paraganglioma. Widespread Phox2B immunoreactivity is a highly characteristic feature of PGs and it can be used as an additional marker in differential diagnosis of neuroendocrine tumours.
