RESUMO
Adrenal paraganglioma (or "pheochromocytoma") and extra-adrenal paraganglioma, collectively abbreviated PPGL, are rare but spectacular nonepithelial neuroendocrine neoplasms. These are the most inheritable neoplasia of all, with a metastatic potential in a varying degree. As of such, these lesions demand careful histologic, immunohistochemical, and genetic characterization to provide the clinical team with a detailed report taking into account the anticipated prognosis and risk of syndromic/inherited disease. While no histologic algorithm, immunohistochemical biomarker, or molecular aberration single-handedly can identify potentially lethal cases upfront, the combined analysis of various risk parameters may stratify PPGL patients more stringently than previously. Moreover, the novel 2022 WHO Classification of Endocrine and Neuroendocrine Tumors also brings some new concepts into play, not least the reclassification of special neuroendocrine neoplasms (cauda equina neuroendocrine tumor and composite gangliocytoma/neuroma-neuroendocrine tumor) previously thought to belong to the spectrum of PPGL. This review focuses on updated key diagnostic and prognostic concepts that will aid when facing this rather enigmatic tumor entity in clinical practice.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasias Encefálicas , Paraganglioma Extrassuprarrenal , Paraganglioma , Neoplasias do Sistema Nervoso Periférico , Feocromocitoma , Humanos , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Neoplasias das Glândulas Suprarrenais/patologia , PrognósticoRESUMO
The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.
Assuntos
Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/patologia , HumanosRESUMO
Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.
Assuntos
Adenoma Oxífilo/genética , Tumor de Células Granulares/genética , Neoplasias Hipofisárias/genética , Epigênese Genética , HumanosRESUMO
The modern classification of pituitary neuroendocrine tumors relies mainly on immunohistochemistry for pituitary transcription factors, hormones, and other biomarkers, including low molecular weight cytokeratins. The transcription factor GATA2 is required for development of gonadotrophs and thyrotrophs but has not been used for classification of pituitary tumors. Because of genomic paralogy of GATA2 and GATA3, we postulated that GATA3 immunohistochemistry may detect GATA2 in the adenohypophysis. We examined 151 tumors originating from Ondokuz Mayis University, Turkey (n = 83) and University Health Network, Canada (n = 68). Initially, 83 tumors (26 gonadotroph, 24 somatotroph, 17 corticotroph, 12 lactotroph, 2 poorly differentiated Pit-1 lineage tumors that expressed TSH and 2 null cell tumors) from Ondokuz Mayis University were investigated with the GATA3 monoclonal antibody L50-823. Retrospective review of the files of University Health Network identified 68 tumors (43 gonadotroph, 3 somatotroph, 2 lactotroph, 1 mammosomatotroph, 9 corticotroph, 7 poorly differentiated Pit-1 lineage tumors with TSH expression, 2 plurihormonal tumors with TSH expression and 1 null cell tumor) that were examined with the same GATA3 antibody and served as a validation cohort. All somatotroph, lactotroph and mammosomatotroph tumors and the null cell tumors were negative for GATA3. Sixty-eight (98.5%) gonadotroph tumors were positive for GATA3; 64 had diffuse reactivity. Two plurihormonal tumors with TSH expression and eight (88.8%) poorly differentiated Pit-1 lineage tumors with variable TSH expression were positive for GATA3. One of 26 (3.8%) corticotroph tumors was diffusely positive for GATA3. This study shows that GATA3 immunoreactivity is characteristic of pituitary gonadotroph and TSH-producing tumors. This finding expands the pattern of transcription factors that are used to classify adenohypophysial tumors and is important in the differential diagnosis of sellar tumors, as GATA3 expression is also a feature of primary sellar paragangliomas as well as carcinomas that may metastasize to the sella.
Assuntos
Biomarcadores Tumorais/análise , Fator de Transcrição GATA3/biossíntese , Tumores Neuroendócrinos/classificação , Neoplasias Hipofisárias/classificação , Fator de Transcrição GATA3/análise , Humanos , Imuno-Histoquímica , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated. METHODS: Patients with PTC and tall cells, defined as having a height-to-width ratio of ≥ 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, ≥ 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome. RESULTS: We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0-5.7) for focal tall cell change, and 3.4 (95% CI 1.2-8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4-98.0) compared with focal tall cell change (76.3%, CI 66.1-86.5) and the tall cell variant (62.2%, CI 43.2-81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10-19%, 20-29% and ≥ 30%), identification of ≥ 10% tall cell change was associated with worse outcome (p = 0.002). CONCLUSIONS: PTCs with ≥ 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification.
Assuntos
Recidiva Local de Neoplasia/patologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/secundário , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Câncer Papilífero da Tireoide/classificação , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.
Assuntos
Hemangioblastoma/genética , Feocromocitoma/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Hemangioblastoma/epidemiologia , Hemangioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Linhagem , Penetrância , Feocromocitoma/epidemiologia , Feocromocitoma/patologia , Adulto Jovem , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/patologiaRESUMO
PURPOSE: The 2017 World Health Organization classification of pituitary tumors redefined pituitary null cell adenomas (NCAs) by restricting this diagnostic category to pituitary tumors that are negative for pituitary transcription factors and adenohypophyseal hormones. The clinical behavior of this redefined entity has not been widely studied, and this is a major shortcoming of the classification. This study evaluated the imaging and clinical features of NCAs from two pituitary centers and compared them with those of gonadotroph adenomas (GAs). METHODS: Imaging, pathologic, and clinical characteristics of NCAs and GAs were retrospectively reviewed. Tumor immunohistochemistry was performed to confirm absence of adenohypophyseal hormones and pituitary transcription factor expression. RESULTS: Thirty-one NCAs were compared with 38 GAs. NCAs were more likely to invade the cavernous sinus (15/31 [48%] vs. 5/38 [13%], P = .003) and had a higher proliferative index (i.e., MIB-1 > 3%, 11/31 [35%] vs. 5/38 [13%], P = .04). Gross total resection was less likely in the NCA group (19/31 [61%] vs. 33/38 [87], P = .02). Progression-free survival was worse in the NCA cohort (5-year progression-free survival, 0.70 vs. 1.00; P = .011, by log-rank test). CONCLUSIONS: Compared with GAs, NCAs are more invasive at the time of presentation and have a more aggressive clinical course. This study provides evidence that NCAs represent a distinct clinicopathologic entity with behavior that differs adversely from that of GAs. This may inform clinical decision-making, including frequency of postoperative tumor surveillance and timing of adjunctive treatments.
Assuntos
Hipófise/diagnóstico por imagem , Hipófise/patologia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos Nulos/patologia , Masculino , Doenças da Hipófise/diagnóstico por imagem , Doenças da Hipófise/mortalidade , Doenças da Hipófise/patologia , Neoplasias Hipofisárias/mortalidade , Intervalo Livre de Progressão , Estudos Retrospectivos , Organização Mundial da SaúdeRESUMO
Recent studies have reported the prevalence of pituitary tumors to be ~1/1000 population. Many are prolactin-producing tumors that are managed medically, however, the epidemiology of surgically resected pituitary adenohypophysial neuroendocrine tumors has not been reported in a large series with detailed characterization. We reviewed 1055 adenohypophysial tumors from 1169 transsphenoidal resections from the pathology files of University Health Network, Toronto, 2001-2016. Tumors were characterized by immunohistochemical localization of transcription factors (Pit-1, ERα, SF-1, Tpit), hormones (adrenocorticotropin, growth hormone, prolactin, ß-thyrotropin, ß-folliculotropin, ß-luteotropin, α-subunit), and other biomarkers (keratins, Ki67, p27, FGFR4). Electron microscopy was used only for unusual lesions. In this cohort, 51.3% of patients were female; the average age was 51 years. Gonadotroph tumors represented 42.5%. Pit-1-lineage-tumors represented 29.9%; these were subclassified as growth-hormone-predominant (somatotroph/mammosomatotroph/mixed; 53%), prolactin-predominant (lactotroph/acidophil-stem-cell; 28%), thyrotrophs (2%), plurihormonal (14%), and not-otherwise-specified (3%). Corticotroph tumors represented 17.1%. Only 4.5% were null cell tumors and 0.5% were unusual plurihormonal tumors. In 5.5% the tumor was not characterized for technical reasons (sample size, fixation, necrosis or other artifact). All corticotroph and plurihormonal tumors were positive for keratins; others tumors showed variable negativity with highest rates in gonadotroph (37.1%) and null cell tumors (28.2%). Tumors with a Ki67 ≥ 3% comprised 60% of this cohort. Global loss of p27 was most frequent in corticotroph neoplasms, specifically those associated with elevated glucocorticoid levels. Corticotroph and lactotroph tumors were more common among females; gonadotroph tumors were more common among males. Younger patients had mainly corticotroph and Pit-1-lineage neoplasms, whereas older patients harbored mainly gonadotroph tumors. This represents one of the largest surgical series of morphologically characterized pituitary tumors reported to date and the first to include the routine use of transcription factors for tumor classification. The data provide the basis for clinicopathologic correlations that are helpful for prognostic and predictive patient management.
Assuntos
Adenoma/epidemiologia , Hipófise/metabolismo , Neoplasias Hipofisárias/epidemiologia , Adenoma/metabolismo , Adenoma/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prevalência , Adulto JovemRESUMO
The rising incidence of papillary thyroid carcinoma is linked in part to inclusion of noninvasive follicular variant of papillary thyroid carcinoma. Despite its designation as carcinoma, noninvasive follicular variant of papillary thyroid carcinoma appears to be exceptionally indolent, often over treated by current treatment practices. Additionally, criteria for diagnosis have historically been subjective and challenging. Recently, an international multidisciplinary collaborative group performed a clinicopathologic survey of such cases with extended follow-up and concluded based on the outcome data that a revision in nomenclature was warranted, proposing 'Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).' This monograph is a synopsis and guide for pathologists on NIFTP and focuses on histologic features, including inclusion and exclusion criteria used to define NIFTP, as well as grossing guidelines, reporting practices, and potential diagnostic limitations.
Assuntos
Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , HumanosRESUMO
The increasing recognition of pituitary disorders and their impact on quality of life and longevity has made understanding of this small gland a subject of paramount importance. Pituitary pathology has seen many significant studies that indicate progress in identification and classification of pituitary lesions, as well as improved management strategies for patients. In this review, we outline six major areas of advances: (i) changes in terminology from 'adenoma' to 'pituitary neuroendocrine tumour'; (ii) reclassification of hormone-negative tumours based on transcription factor expression that defines lineage; (iii) updates in new pathogenetic mechanisms, including those that underlie rare lesions such as X-LAG and pituitary blastoma; (iv) clarification of hypophysitis due to immunotherapy, xanthomatous hypophysitis due to rupture of a Rathke's cleft cyst and IgG4 disease as the cause of inflammatory pseudotumour; (v) the consolidation of pituicytoma variants, including spindle cell oncocytoma and granular cell tumour based on thyroid transcription factor-1 (TTF-1) reactivity; and (vi) the pathogenetic mechanisms that distinguish papillary from adamantinomatous craniopharyngioma. The remaining challenge is clarification of the pathogenetic mechanisms underlying the development of many of these disorders.
Assuntos
Patologia Clínica/tendências , Doenças da Hipófise/patologia , Hipófise/patologia , HumanosRESUMO
BACKGROUND: Renaming encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently suggested to prevent the overtreatment, cost and stigma associated with this low-risk entity. The purpose of this study is to document the incidence and further assess the clinical outcomes of reclassifying EFVPTC to NIFTP. METHODS: We searched synoptic pathologic reports from a high-volume academic endocrine surgery hospital from 2004 to 2013. The standard of surgical pathology practice was based on complete submission of malignant thyroid nodules along with the nontumorous thyroid parenchyma. Rigid morphological criteria were used for the diagnosis of noninvasive EFVPTC, currently known as NIFTP. A retrospective chart review was conducted looking for evidence of malignant behavior. RESULTS: One hundred and two patients met the strict inclusion criteria of NIFTP. The incidence of NIFTP in our cohort was 2.1% of papillary thyroid cancer cases during the studied time period. Mean follow-up was 5.7 years (range 0-11). Five patients were identified with nodal metastasis and one patient with distant metastasis. Overall, six patients showed evidence of malignant behavior representing 6% of patients with NIFTP. CONCLUSION: Our study demonstrates that the incidence of NIFTP is significantly lower than previously thought. Furthermore, evidence of malignant behavior was seen in a significant number of NIFTP patients. Although the authors fully support the de-escalation of aggressive treatment for low-risk thyroid cancers, NIFTP behaves as a low-risk thyroid cancer rather than a benign entity and ongoing surveillance is warranted.
Assuntos
Carcinoma Papilar, Variante Folicular/patologia , Carcinoma Papilar/patologia , Terminologia como Assunto , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/classificação , Carcinoma Papilar, Variante Folicular/epidemiologia , Feminino , Humanos , Incidência , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/classificação , Nódulo da Glândula Tireoide/patologia , Tireoidectomia , Adulto JovemRESUMO
Thyroid tumors formerly classified as non-invasive encapsulated follicular variant of papillary thyroid carcinoma were recently renamed 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features'. The current study investigated the frequency of lymph node metastasis and mutational profile of encapsulated follicular variant in the setting of a clinical practice where central neck dissection was the standard of practice. We defined the impact of rigid diagnostic criteria by regrouping such tumors based on the complete absence of papillae or presence of ≤1% papillae. Of a total of 6,269 papillary thyroid carcinomas, 152 tumors fulfilled the criteria for encapsulated follicular variant. The results were stratified according to two different diagnostic cutoff criteria with respect to the extent of papillae. When the cutoff of 1% papillae was used, the rates of lymph node metastasis and BRAFV600E mutation were 3% and 10% in non-invasive tumors and 9% and 4% in invasive tumors, respectively. Despite the lack of invasive growth, one patient with BRAFV600E mutant-tumor displaying predominant follicular growth and subtle papillae developed a bone metastasis. When absence of papillary structure was applied as rigid diagnostic criteria, no BRAFV600E mutation was found in all tumors. However, central lymph node micrometastasis still occurred in 3% of non-invasive tumors. Non-V600E BRAF and RAS mutations were detected in 4% and 47% of non-invasive tumors, respectively. Our findings suggest that non-invasive follicular thyroid neoplasm with papillary-like nuclear features should not be regarded as a benign thyroid neoplasm as it can present with lymph node micrometastasis and should not be diagnosed in the presence of even a single papillary structure. Our findings underscore the original American Thyroid Association recommendation that defined non-invasive encapsulated follicular variants as low risk thyroid cancers. Clinical surveillance similar to low risk differentiated thyroid cancers and capture of this diagnostic category by Cancer Registries should be considered.
Assuntos
Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/secundário , Biomarcadores Tumorais/genética , Carcinoma Papilar/genética , Carcinoma Papilar/secundário , Mutação , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/cirurgia , Análise Mutacional de DNA , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Metástase Linfática , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto JovemRESUMO
AIMS: The current World Health Organization classification categorises high-grade neuroendocrine (NE) carcinomas of the prostate into small-cell and large-cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features. METHODS AND RESULTS: Five cases of high-grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate-specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small-cell or large-cell NE carcinoma were absent. As compared with conventional high-grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate-specific acid phosphatase, combined with diffuse or confluent/non-focal positivity for chromogranin-A and synaptophysin. Two hormone-naive cases showed a clinical response to androgen deprivation therapy. CONCLUSION: This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma/patologia , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Carcinoma Neuroendócrino/metabolismo , Diferenciação Celular , Cromogranina A/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Sinaptofisina/metabolismoRESUMO
Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 µg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1-9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2-171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our findings argue against the use of the nomenclature 'silent' for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as 'poorly differentiated Pit-1 lineage adenomas'.
Assuntos
Adenoma/química , Biomarcadores Tumorais/análise , Diferenciação Celular , Linhagem da Célula , Neoplasias Hipofisárias/química , Fator de Transcrição Pit-1/análise , Acromegalia/etiologia , Adenoma/classificação , Adenoma/complicações , Adenoma/cirurgia , Adenoma/ultraestrutura , Adolescente , Adulto , Idoso , Amenorreia/etiologia , Feminino , Galactorreia/etiologia , Humanos , Hipertireoidismo/etiologia , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasia Residual , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/ultraestrutura , Valor Preditivo dos Testes , Estudos Retrospectivos , Terminologia como Assunto , Resultado do Tratamento , Adulto JovemAssuntos
Adenoma , Tumores Neuroendócrinos , Doenças da Hipófise , Neoplasias Hipofisárias , Humanos , HipófiseRESUMO
Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease.
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Appendiceal neuroendocrine tumors (NETs) are common and often are identified as incidental lesions at the time of appendectomy. The guidelines for management are based on tumor size, degree of invasion, and the Ki67 proliferation index. Most small bowel NETs are composed of serotonin-producing EC-cells, but there are multiple other neuroendocrine cell types. In the rectum, there are L-cell tumors that express peptide YY (PYY), glucagon-like peptides (GLPs), and pancreatic polypeptide (PP); they are thought to have a better prognosis than serotonin-producing tumors. We investigated whether the appendix has distinct neuroendocrine tumor types based on cell type and whether that distinction has clinical significance. We collected 135 appendiceal NETs from the pathology archives of UHN Toronto and UHCMC (Cleveland). We analyzed the expression of biomarkers including CDX2, SATB2, PSAP, serotonin, glucagon (that detects GLPs), PYY, and pancreatic polypeptide (PP) and correlated the results with clinicopathologic parameters. Immunohistochemistry identified three types of appendiceal NETs. There were 75 (56%) classified as EC-cell tumors and 37 (27%) classified as L-cell tumors; the remaining 23 (17%) expressed serotonin and one of the L-cell biomarkers and were classified as mixed. EC-cell tumors were significantly larger with more extensive invasion involving the muscularis propria, subserosa, and mesoappendix compared with L-cell tumors. Mixed tumors were intermediate in all of these parameters. Both EC-cell and mixed tumors had lymphatic and/or vascular invasion while L-cell tumors had none. Unlike EC-cell NETs, L-cell tumors were not associated with lymph node metastasis. Tumor type correlated with pT stage and the only patient with distant metastatic disease in this series had an EC-cell tumor. Our study confirms that appendiceal NETs are not a homogeneous tumor population. There are at least three types of appendiceal NET, including EC-cell, L-cell, and mixed tumors. This information is important for surveillance of patients, as monitoring urinary 5HIAA levels is only appropriate for patients with serotonin-producing tumors, whereas measurement of GLPs and/or PP is more appropriate for patients with L-cell tumors. Our data also show that tumor type is of significance with EC-cell tumors exhibiting the most aggressive behavior.
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Neoplasias do Apêndice , Biomarcadores Tumorais , Tumores Neuroendócrinos , Humanos , Neoplasias do Apêndice/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Biomarcadores Tumorais/análise , Idoso de 80 Anos ou mais , Adulto Jovem , Imuno-HistoquímicaRESUMO
OBJECTIVE: The association between autoimmunity-related tissue injury and thyroid cancer development remains an area of interest. Evidence suggests that patients with Graves disease (GD) may have an elevated risk for differentiated thyroid cancer. Multicenter studies are needed to gain insight into the correlates of papillary thyroid carcinoma (PTC) identified in this particular group of patients. This study aimed to investigate the prevalence of PTC and synchronous thyroid nodules in thyroidectomy specimens from GD patients in an endemic goiter region. MATERIAL AND METHODS: A retrospective review of institutional pathology records at two tertiary care centers identified 237 surgically treated patients with GD. Patients were categorized as having nodular Graves disease (N-GD) if synchronous nodular thyroid was identified by ultrasonography, while those without synchronous thyroid nodules were categorized as non-nodular or simple Graves disease (S-GD). The prevalence of PTC, histopathological correlates, and demographic characteristics were recorded and compared between groups N-GD and S-GD. RESULTS: One hundred thirty-one and 106 patients were assigned to N-GD and S-GD, respectively. The mean age was significantly higher in N-GD (mean 45.52 years) compared to S-GD (mean 35.18 years) (p < 0.001). The overall frequency of PTC was 36.3% (86/237) in the entire cohort. PTC was identified in 48.1% (63/131) of N-GD and 21.7% (23/106) of S-GD (p < 0.001). Subcentimeter tumors constituted the majority of cases in both groups (76.2% in N-GD and 82.6% in S-GD) (p > 0.05). The group of S-GD was enriched in BRAF-like PTCs, whereas N-GD had equal distribution for RAS- and BRAF-like tumors. CONCLUSION: This study underscores that the majority of PTCs encountered in GD were enriched in low-risk subcentimeter PTCs with a prevalence that varies depending on the presence of underlying nodular thyroid tissue.
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Unlike somatotroph tumors, the data on correlates of tumor granulation patterns in functional TPIT lineage pituitary neuroendocrine tumors (corticotroph tumors) have been less uniformly documented in most clinical series. This study evaluated characteristics of 41 well-characterized functional corticotroph tumors consisting of 28 densely granulated corticotroph tumors (DGCTs) and 13 sparsely granulated corticotroph tumors (SGCTs) with respect to preoperative clinical and radiological findings, tumor proliferative activity (including mitotic count and Ki-67 labeling index), and postoperative early biochemical remission rates. The median (interquartile range (IQR)) tumor size was significantly larger in the SGCT group [16.00 (16.00) mm in SGCT vs 8.5 (9.75) mm in DGCT, p = 0.049]. T2-weighted signal intensity and T2 intensity (quantitative) did not yield statistical significance based on tumor granulation; however, the T2 intensity-to-white matter ratio was significantly higher in SGCTs (p = 0.049). The median (IQR) Ki-67 labeling index was 2.00% (IQR 1.00%) in the DGCT group and 4.00% (IQR 7.00%) in the SGCT group (p = 0.043). The mitotic count per 2 mm2 was higher in the SGCT group (p = 0.001). In the multivariate analysis, the sparse granulation pattern (SGCT) remained an independent predictor of a lower probability of early biochemical remission irrespective of the tumor size and proliferative activity (p = 0.012). The current study further supports the impact of tumor granulation pattern as a biologic variable and warrants the detailed histological subtyping of functional corticotroph tumors as indicated in the WHO classification of pituitary neuroendocrine tumors. More importantly, the assessment of the quantitative T2 intensity-to-white matter ratio may serve as a preoperative radiological harbinger of SGCTs.
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Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.