Endocrine Pathology最新文献

Functioning pancreatic neuroendocrine tumors (PanNETs) represent a subset of PanNETs that cause symptoms due to hormonal activity. Insulinoma is the most common functioning PanNET type. Mutations in the alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes result in genomic instability. ATRX/DAXX mutations and associated alternative lengthening of telomeres (ALT) are common in non-functioning PanNETs and associated with aggressive tumor behavior. Recent reports have shown that ATRX/DAXX mutations and ALT are also present in functioning PanNETs. In this review, we summarize the literature addressing ATRX/DAXX mutations and ALT in functioning PanNETs and discuss the clinical relevance with regard to distinguishing aggressive and indolent functioning tumors. ATRX/DAXX gene mutations and/or ALT have been reported in insulinoma, glucagonoma, gastrinoma, VIPoma and calcitoninoma. In insulinoma, the presence of ATRX/DAXX mutations and ALT are associated with aggressive behavior and could therefore be used as prognostic biomarkers. Although ATRX/DAXX mutation and ALT assessment may currently not be the standard of care in routine diagnostic pathology practice, the use of DAXX/ATRX immunohistochemistry at least can be encouraged not only for non-functioning but also for functioning PanNETs.

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms that include tumors with different histomorphologic characteristics that can be correlated to sub-categories with different prognoses. In addition to the WHO grading scheme based on tumor proliferative activity, a new parameter based on the scoring of infiltration patterns at the interface of tumor and non-neoplastic parenchyma (tumor-NNP interface) has recently been proposed for PanNET categorization. Despite the known correlations, these categorizations can still be problematic due to the need for human judgment, which may involve intra- and inter-observer variability. Although there is a great need for automated systems working on quantitative metrics to reduce observer variability, there are no such systems for PanNET categorization. Addressing this gap, this study presents a computational pipeline that uses deep learning models to automatically categorize PanNETs for the first time. This pipeline proposes to quantitatively characterize PanNETs by constructing entity-graphs on the cells, and to learn the PanNET categorization using a graph neural network (GNN) trained on these graphs. Different than the previous studies, the proposed model integrates pathology domain knowledge into the GNN construction and training for the purpose of a deeper utilization of the tumor microenvironment and its architectural changes for PanNET categorization. We tested our model on 105 HE stained whole slide images of PanNET tissues. The experiments revealed that this domain knowledge integrated pipeline led to a 76.70% test set F1-score, resulting in significant improvements over its counterparts.

Merkel cell carcinoma (MCC) is diagnosed through histopathological and immunohistochemical examination of biopsies from skin or other organs. Its distinguishing features include perinuclear dot-like staining with Cytokeratin 20 (CK20) and detection of Merkel cell polyomavirus (MCPyV) using various methods. However, CK20 and MCPyV negative MCC cases have been reported at varying rates. In this single center cross-sectional study, we aimed to determine which clones are more effective in diagnosing MCC by comparing the performance of CK20 antibody clones Ks20.8 and SP33, as well as MCPyV antibody clones Ab3 and CM2B4. Fifty-four patients diagnosed with MCC were included. Among these, 42 cases were primary cutaneous, and 12 cases were nodal MCC. Fifty-two (96.3%) cases were positive with both CK20 clones, while two cases were negative. Clone SP33 stained areas of necrosis, whereas Ks20.8 showed no aberrant staining. MCPyV was detected in 44 cases (81.5%) using clone Ab3 and 39 cases (72.2%) using clone CM2B4. Staining with MCPyV clone Ab3 was diffuse and strong in most cases, while approximately 30% of CM2B4-positive cases exhibited low percentages and/or weak staining, complicating the evaluation. The two CK20-negative cases were also negative with both MCPyV clones. Our data demonstrated that CK20 clone Ks20.8 may be preferred for MCC diagnosis due to its consistent performance and lack of aberrant staining. Similarly, MCPyV clone Ab3 appears superior to CM2B4 for identifying MCPyV-positive cases.

Inhibiting the immune checkpoint (ICP) PD-1 based on PD-L1 expression status has revolutionized the treatment of various cancers, yet its efficacy in anaplastic thyroid carcinoma (ATC) remains limited. The therapeutic response depends upon multiple factors, particularly the conduciveness of the tumor's immune milieu. This study comprehensively evaluated and classified ATC's immune microenvironment (IME) to elucidate the factors behind suboptimal response to anti-PD therapy. Utilizing multiplex-immunofluorescence and immunohistochemistry, we retrospectively analyzed 26 cases of ATC for expression of ICPs PD-L1, PD-1, CTLA4, TIM3, and Galectin-9 and tumor-infiltrating cytotoxic T lymphocytes (CTL)-the effector cells, the anti-tumor NK cells, the immune-inhibitory myeloid-derived suppressor (MDSC) and regulatory T (Treg) cells, and B lymphocytes. Most ATCs (65%) exhibited PD-L1 positivity, but only 31%, in addition, had abundant CTL (type I IME), a combination associated with a better response to ICP inhibition. Additionally, PD-1 expression levels on CTL were low/absent in most cases-a "target-missing" situation-unfavorable for an adequate therapeutic response. All but one ATC showed nuclear Galectin-9 expression. The documentation of nuclear expression of Galectin-9 akin to benign thyroid is a first, and its role in ATC pathobiology needs further elucidation. In addition to less abundant PD-1 expression on CTL, the presence of MDSC, Treg, and exhausted cytotoxic T lymphocytes in the immune milieu of ATC can contribute to anti-PD resistance. TIM3, the most frequently expressed ICP on CTL, followed by CTLA4, provides alternate therapeutic targets in ATC. The co-expression of multiple immune checkpoints is of great interest for ATC since these data also open the avenue for combination therapies.

Oncocytic thyroid tumors are characterized by an elevated mitochondrial density within the cells, distinguishing them from other thyroid tumors, exhibit distinct clinical behaviors, including increased invasiveness and iodine therapy resistance. However, the proteomic alterations in oncocytic thyroid tumors remain inadequately characterized. In this study, we analyzed 156 Asian patients with oncocytic thyroid adenomas (OA) and carcinomas (OCA) to explore their clinical, genetic, and proteomic features. Genetic testing of 73 samples revealed frequent mutations in TERT, NRAS, EIF1AX, EZH1, and HRAS, with TERT promoter mutations being exclusive to OCAs. Proteomic analysis identified 66 mitochondrial-specific proteins significantly highly expressed in oncocytic tumors than in non-oncocytic tumors. This led to the development of a thyroid oncocytic score (TOS) to quantify oncocytic characteristics. Among these proteins, isocitrate dehydrogenase 2 (IDH2) was substantially overexpressed in oncocytic tumors and further confirmed by immunohistochemistry in oncocytic tumor slides (n = 41) and non-oncocytic tumor slides (n = 40). Moreover, IDH2 is significantly overexpressed in OCA compared to OA highlighting its potential as a biomarker for differential diagnosis of oncocytic tumors and malignancy. These findings improve the understanding of oncocytic thyroid tumors molecular pathology and suggest IDH2 as a valuable marker for clinical management.

Formalin-fixed paraffin-embedded (FFPE) tissue samples are important for genomic analysis of thyroid carcinomas, particularly for various molecularly targeted therapies. Therefore, this study developed and validated a technique for preparing FFPE tissue samples that preserves nucleic acid quality, which is fundamental for precise genomic analysis, more effectively than conventional methods. We analyzed surgically resected thyroid gland tumors, lymph node metastases, and separately fixed tumor samples to optimize formalin fixation and assess the influence of specimen type and preparation methods on nucleic acid quality. We assessed several quality indicators, including the DNA integrity number, cycle threshold ratio, RNA integrity number, and DV200. Separately fixed tumor samples consistently exhibited higher DNA and RNA quality than conventionally processed samples. Additionally, lymph node metastases often exhibit nucleic acid quality matching or exceeding that of thyroid gland tumors, highlighting their potential reliability for genomic analysis. These findings suggest the utility of various specimen types for the comprehensive genetic profiling of thyroid carcinomas. In conclusion, this study demonstrated that preparing separately fixed tumor samples is an effective method for preserving DNA and RNA quality for genomic analyses. Biopsy punches enable specimen collection at various facilities, including those without the ability to handle frozen specimens. This contributes to the development of a method for obtaining high-quality pathological samples that can be widely used in general medical practice. Moreover, lymph node metastases often exhibit nucleic acid quality equal to or superior to that of thyroid gland tumors, highlighting their potential as acceptable sources for genomic analyses.

Thyroid cancer management is rapidly changing. The identification of actionable biomarkers through both germline and somatic testing are now an integral part of directing patient management. However, deficiencies and disparities within existing thyroid cancer biomarker test approaches are resulting in inconsistent application for patient care. An expert panel was convened to create consensus biomarker testing algorithms and recommendations on actionable biomarker testing for patients diagnosed with medullary thyroid cancer, non-anaplastic follicular cell-derived thyroid cancer, or anaplastic follicular cell-derived thyroid cancer who may benefit from targeted therapies. A review of international guidelines was performed to determine the current state, and a literature review was carried out to further evaluate the evidence supporting the use of actionable biomarkers in patients diagnosed with thyroid cancer. Thyroid biomarker-related gaps impacting patient care were also discussed, with an emphasis on the importance of a multidisciplinary team approach for optimal patient care. The recommendations are presented with the aim to help physicians navigate the current thyroid cancer biomarker testing landscape with its many challenges, balancing aspirational care with what is practical and feasible in terms of economic realities and jurisdictional constraints. By remaining therapy-agnostic, these algorithms and recommendations are broadly applicable.

Little is known about the morphomolecular features of G3 neuroendocrine tumors (G3NETs) under prolonged systemic treatments, although rapid progression is increasingly observed. This longitudinal study aims to elucidate the course and morphomolecular features of metastasized G3NETs with high-grade transformation. Clinical and histological findings in 40 patients with metastasized and treated G3NETs, which were histologically examined at least twice with an interval time of more than 6 months (median 27), were reviewed and the morphomolecular changes recorded and assigned to treatment. Neuroendocrine carcinoma (NEC)-like histology defined by high-grade atypia, diffuse growth pattern, and/or necrosis was identified in nine (22%) G3NETs (seven pancreatic, two rectal) patients. All NEC-like tumors showed a significantly higher Ki67 increase and longer interval time between first and last examination than non-NEC-like G3NETs (53 vs. 19% and 60 vs. 24 months, respectively). Moreover, all NEC-like G3NETs had TP53 (100%), but rarely RB1 (12%) mutations, and retained NET-typical mutations such as MEN1 or DAXX (five of the pancreatic NETs). The last treatments received prior to the NEC-like transformation included PRRT (n = 3), somatostatin analog, everolimus, sunitinib (n = 1 each), and alkylating agents (n = 2). Abrupt clinical progression in patients with metastasized G3NETs is associated with a significant increase in Ki67, accelerated growth, and NEC-like histology. These findings are most likely attributable to the novel TP53 mutation, which was detected in all nine cases at the last evaluation. However, none of the cases exhibited a complete transformation to a typical NEC, as the tumors retained partial histological and genetic features of NETs.

Medullary thyroid carcinoma (MTC) can either be sporadic, often via mutually exclusive RET or RAS alterations, or inherited via a RET germline alteration. Germline testing is recommended for all patients diagnosed with MTC. RAS p.Q61R immunohistochemistry (RASQ61R-IHC) can identify a subset of RAS-mutated MTCs on resections, but whether this could be applied pre-operatively to cytology specimens remains unclear. Herein, we assessed RASQ61R-IHC in a tri-institutional cohort of cytologic and histologic MTC specimens with available molecular and germline data. Thirty-four fine needle aspirates with cell blocks were identified between three institutions from 2009 to 2024 with corresponding histology. Tumor sequencing and germline data were recorded, if available. RASQ61R-IHC was scored on staining intensity with documentation of membranous accentuation. Sensitivity, specificity, positive predictive (PPV), and negative predictive values (NPV) were calculated. Of the MTCs, 29% were germline-mutated, and 71% were sporadic. Among all sporadic MTCs (n = 22), 41% were RET-altered, 27% were RAS-altered, and 31.8% did not have available data. With any RASQ61R-IHC staining considered positive, sensitivity, specificity, PPV, and NPV for detecting RAS p.Q61R-mutated MTCs were 100%, 72.7%, 45.4%, and 100%, respectively. Requiring a stain score of > 1 and/or membranous accentuation for a true positive changed sensitivity, specificity, PPV, and NPV to 100%, 100%, 100%, and 100%, respectively. RASQ61R-IHC membranous staining was 100% predictive of RET-negative germline testing. RASQ61R-IHC, when requiring a score > 1 and/or membranous stain accentuation for true positive, had high sensitivity and specificity for RAS p.Q61R mutation in cytologic and surgical MTC specimens. Moreover, RASQ61R-IHC is a rapid and inexpensive modality that could potentially tailor which MTC patients undergo germline testing.

Tumors of adenohypophysial hormone-secreting cells, now classified as pituitary neuroendocrine tumors (PitNETs), have been subclassified based on cell differentiation. Normal adenohypophysial cells have three lineages of differentiation driven by the transcription factors PIT1, TPIT, and SF1 which are responsible for the regulation of hormone gene expression; PIT1 drives expression of GH, PRL, and TSH, TPIT is required for POMC expression that gives rise to ACTH, and SF1 is the transcription factor responsible for FSH and LH expression. The vast majority of PitNETs follow these three lineage differentiation pathways but rare PitNETs show either no lineage differentiation or express biomarkers of more than one lineage. The recent WHO classification continued the terminology "plurihormonal" for tumors that have features of more than one lineage but a better term is "multilineage" since some tumors may express more than one lineage-specific transcription factor without the hormones that are driven by those factors. Recent data indicate that tumors with expression of PIT1 and SF1 are the most common multilineage PitNETs. Here we report the existence of rare PitNETs that express TPIT and SF1. The 6 patients (5 female, 1 male; mean age 54.8 years; range 35-84 years) represent less than 1% of patients in our series of PitNETs. Most patients had clinically silent tumors with no evidence of hormone excess and variable degrees of hypopituitarism; two had Cushing disease. All patients had macrotumors with a mean tumor size of 2.46 cm (range 1.1-5.0 cm). Crooke's hyaline change was identified in the nontumorous adenohypophysis of the two patients with Cushing disease. The mean Ki67 labeling index was 2.91% (range 2.03-3.94%). All tumors were negative for PIT1 and PIT1-lineage hormones (GH, PRL, and TSH). TPIT was focal in one tumor, and the remaining tumors had diffuse reactivity in more than 50% of tumor cells. SF1 expression was focal in 5 tumors and diffuse in one. Three tumors had variable expression of at least one gonadotropin (FSH or LH). GATA3 was expressed in two tumors. Variable ER-alpha expression was noted in three tumors. CAM5.2 was positive in all tumors. With the exception of two tumors causing Cushing disease, p27 expression was intact. Our study confirms that multilineage PitNETs expressing TPIT and SF1 occur but are extremely rare; they can be clinically non-functional or can cause Cushing disease. Irrespective of functional status of a PitNET, routine application of pituitary transcription factors is warranted to identify these tumors. Data on the molecular correlates and clinical significance are still needed for these rare multilineage PitNETs.