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Editorial
Agressive pituitary tumours: A diagnostic and therapeutic challenge for multidisciplinary pituitary units
Tumores adenohipofisarios agresivos: Reto diagnóstico y terapéutico para las Unidades Multidisciplinares de Excelencia en Patología Hipofisaria
Antonio Picó
Servicio de Endocrinología y Nutrición, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante –ISABIAL, Universidad Miguel Hernández, 03010 Alicante, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Iglesias P et al&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> recently published a review of the multimodal treatment of aggressive pituitary tumors&#46; After introducing the concept of aggressiveness based on clinical&#44; radiographic&#44; and histological criteria&#44; they identified the subtypes of pituitary tumors most commonly related to an aggressive behavior and analyzed the pathological pathways involved in their development that justify the different therapeutic strategies used&#46; They finally emphasized the need for multidisciplinary treatment of these tumors in centers of excellence that have the resources and experience to ensure the best possible results&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">But are aggressive pituitary tumors well defined&#63; Are they amenable to a therapeutic approach different to that for other pituitary tumors&#63;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Adenopituitary tumors usually exhibit a benign behavior and have therefore been considered as adenomas&#46; It has recently been proposed that they are called pituitary neuroendocrine tumors<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> because they share histological characteristics with extrapituitary neuroendocrine tumors&#46; But clinical sectors in the neuroendocrinology field do not agree with this proposal of the International Pituitary Pathology Club by just because of their indolent behavior&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> However&#44; some of these tumors relapse&#44; compress adjacent anatomical structures&#44; and metastasize&#46; This raises two problems&#58; 1&#46; There must be specific criteria defining the concept of &#8220;aggressiveness&#8221; in pituitary tumors&#44; and 2&#46; An action plan for them should be established&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The 2004 WHO classification stratified three subcategories of pituitary adenomas based on the aggressiveness of their behavior&#58; typical adenoma&#44; atypical adenoma&#44; and carcinoma&#46; Atypical adenomas were defined based on pathological criteria only&#58; high mitotic index&#44; a Ki-67 proliferation rate greater than 3&#37;&#44; and strong staining for p53&#46; Over the subsequent 10 years&#44; these criteria were shown to be inadequate because their prognostic significance could not be established&#46; The 2017<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> WHO classification therefore excluded the atypical adenoma subtype&#46; It admitted however the existence of high-risk pituitary tumors and maintained the recommendation to measure tumor proliferation markers as indicators of aggressiveness&#46; But are these markers equally applicable to all subtypes of pituitary tumors&#63; Are pathological criteria sufficient to define a pituitary tumor as aggressive&#63;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Poorly granulated somatotropic tumors&#44; lactotropic tumors in males&#44; Crooke cell tumors&#44; silent corticotropic tumors&#44; and PIT-1 plurihormonal tumors are known to have a more aggressive behavior than all other subtypes of adenopituitary endocrine tumors&#46; In fact&#44; in 2014 Trouillas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> proposed a clinical-pathological prognostic classification based on tumor subtype and size and on a grading that considered the presence of radiographic invasion &#40;magnetic resonance imaging&#41; and tumor proliferation based on mitotic count and the strength of staining for Ki-67 and p53&#46; A little later&#44; Kovacs et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> replied that the clinical-pathological classification proposed by Jacqueline Trouillas was not applicable to all tumors&#44; stressing the need for a standardized and simplified classification that would allow pathologists not specialized in pituitary morphology to make a faithful diagnosis of pituitary tumors&#46; The authors suggested that hematoxylin and eosine staining and immunostaining for adenopituitary hormones&#44; low molecular weight cytokeratins&#44; and the Ki-67 nuclear index were not sufficient&#46; Finally&#44; in 2018 the European Society of Endocrinology clinical guidelines<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> on aggressive pituitary tumors stated that the definition of aggressiveness of these tumors should be based on their clinical and radiographic presentation and on their behavior during follow-up &#40;rapid growth&#44; refractoriness to treatment&#44; and tendency to relapse&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">While the proposal to introduce clinical variables in the aggressiveness diagnostic equation is reasonable&#44; the concept of &#8220;rapid growth&#8221; should be quantified&#46; In the absence of consensus in the literature&#44; it may be appropriate to use the RECIST criteria<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> to assess the growth of a pituitary tumor&#46; According to this classification&#44; an increase in tumor size of 20&#37; or greater should be considered significant&#44; and a 5&#8239;mm increase would have clinical and therapeutic connotations&#46; However&#44; 5&#8239;mm is excessive in the case of pituitary adenomas&#44; and 2&#8239;mm increases appear more appropriate&#46; To define &#8220;growth&#8221;&#44; the RECIST criteria use the lowest sum of tumor diameters at baseline&#46; However&#44; the irregular shape of pituitary tumors makes it difficult to identify the three smallest diameters&#46; Luckily&#44; it has recently been shown that the response of the largest diameter of a pituitary tumor to treatment correlates with volumetric response&#44; and can be used in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The concept of invasion should also be defined as accurately as possible&#46; The invasion and aggressiveness criteria are sometimes mistakenly exchanged&#46; On the one hand&#44; there are widely invasive tumors with an indolent behavior&#46; On the other hand&#44; all aggressive tumors are invasive&#44; and invasion is the most important clinical feature because it conditions complete surgical resection of the tumor and is associated to a greater likelihood of recurrence or relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Invasion has historically been defined based on pathological&#44; radiological&#44; and surgical evidence&#46; However&#44; microscopic invasion of dura mater is present in most macroadenomas&#44; as well as in some microadenomas&#44; and is not correlated to tumor behavior after surgery&#46; By contrast&#44; there appears to be a good correlation between the invasion detected during endoscopic surgery and that established radiographically&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> with these two parameters being possibly sufficient to define a pituitary tumor as invasive&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Finally&#44; pathological markers of proliferation should be clearly established&#46; The criteria in the 2004 WHO classification &#40;Ki-67&#8239;&#62;&#8239;3&#37;&#44; strong p53 staining&#44; and increased mitotic activity&#41; have not been prospectively validated in the clinical setting&#46; In fact&#44; different Ki-67 thresholds ranging from 3&#37; and 10&#37; have been proposed&#46; However&#44; although there are pituitary tumors with low Ki-67 indices showing an aggressive behavior&#44; most of these have Ki-67 ratios greater than 10&#37;&#44; as compared to the Ki-67 levels of 1&#37;&#8211;3&#37; seen in slowly growing tumors&#46; The recommendation to continue using this marker is therefore maintained&#46; However&#44; attention should be paid to the type of antibody used for its detection and the method to fix the preparation&#44; and the estimate should be replaced by the absolute count&#44; using for this the appropriate programs&#46; The other proliferation indices&#44; a mitotic count &#62;2 and p53 staining intensity &#62;10 nuclei per 10 fields&#44; also have observer-related methodological limitations&#46; A recent European Endocrine Society survey of 93 aggressive pituitary tumors and 34 carcinomas found Ki-67 values &#8805;3&#37; in 81&#37; and 85&#37;&#44; strong &#40;&#62;10&#41; positivity for p53 in 73&#37; and 78&#37;&#44; and mitotic counts &#62;2 mitoses per 10 fields in 63&#37; and 90&#37; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Based on these findings&#44; routine assessment of Ki-67 and the other two markers is recommended only when the index is &#8805;3&#37;7&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The second question is whether aggressive tumors are amenable to a different therapeutic strategy than other pituitary tumors&#46; Surely&#44; yes&#46; The presence of invasion and the tendency to relapse of these tumors makes it highly advisable that they be operated on by surgical teams of proven experience&#44; and that repeat surgery is performed as often as required to reduce local compression symptoms&#46; Adjuvant radiotherapy should not be delayed when tumor growth or hormone hypersecretion cannot be controlled by surgery&#46; Finally&#44; other medical treatments should be used&#44; as these tumors are usually refractory to somatostatin analogues or dopamine agonists&#46; Although specific cases of response to systemic chemotherapy&#44; to inhibitors of the vasoendothelial growth factor &#40;bevacizumab&#41;&#44; the mTOR pathway &#40;everolimus&#41;&#44; or tyrosine kinase &#40;lapatinib&#41;&#44; and to peptide receptor radionuclide therapy agents &#40;<span class="elsevierStyleSup">111</span>In-DTPA-octreotide&#44; <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#44; <span class="elsevierStyleSup">177</span>Lu-DOTATOC&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> 90Yttrium-DOTATE&#41; have been reported&#44; it is still recommended to use temozolamide alone as first-line chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Temozolamide was first used in 2006&#44; and subsequent series have confirmed its efficacy&#44; reporting disease stabilization rates in aggressive adenomas and carcinomas of 29&#37; and 17&#46;4&#37; respectively after 5&#46;5&#8211;120 months of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> These results have been supported by a recent survey by the European Endocrine Society&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; it will be necessary to wait for the results with the immune checkpoint inhibitors CTLA-4 and PD-1&#44; for which there have already been some reports&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In conclusion&#44; according to Pedro Iglesias et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> not all pituitary tumors have an indolent behavior&#44; and some of them pose a significant diagnostic and therapeutic challenge&#46; This justifies the positioning of the Pituitary Society&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> which recommends that a condition of such low prevalence but very high complexity be treated by units of excellence with proven experience in pituitary disease&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Pic&#243; A&#46; Tumores adenohipofisarios agresivos&#58; Reto diagn&#243;stico y terap&#233;utico para las Unidades Multidisciplinares de Excelencia en Patolog&#237;a Hipofisaria&#46; Endocrinol Diabetes Nutr&#46; 2020&#59;67&#58;75&#8211;77&#46;</p>"
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