Endocrine Pathology最新文献

Bilateral macronodular adrenocortical disease (BMAD) is a neoplastic disease associated with a high frequency of germline disease. Armadillo repeat containing 5 (ARMC5) pathogenic variants (PVs) have not been widely studied to determine the morphological and immunohistochemical characteristics of BMAD. We carried out a detailed morphologic review of 22 surgical specimens excised from patients with BMAD and compared them with PV of ARMC5 (PV + , n = 14) and those without (PV - , n = 8), and further comparing them with a control group of adrenals excised from patients with renal cancer (n = 11). No patients presented with a genetic syndrome related to BMAD. Overt Cushing's syndrome was present in 12/22 patients, 10 PV + and 2 PV - (p = 0.074). We also evaluated the expression of Ki-67, BCL-2, BAX, p53, CYP11B1, and ARMC5 protein. The pseudo-glandular and trabecular architectural patterns were strongly associated with the PV + group (both p < 0.001), as well as capsular extrusion (p < 0.001). There was no predictive value in the distinction of ARMC5 variants in Hsiao subtyping. ARMC5 diffuse cytoplasmic staining was observed in all 11 control samples. The ARMC5 expression was significantly lower in BMAD than in the control group (p < 0.001). In all the specimens, expression of BCL-2 was identified only in the medulla, and expression of BAX was observed in adrenocortical cells. CYP11B1 diffuse immunoexpression was identified in all the specimens of BMAD and in the fasciculata zone in the control group. The mitotic count and Ki-67 proliferation index was very low in all three groups (controls, PV + , and PV - BMAD). None of the specimens stained positive for the p53 protein. Although our series is limited, the presence of pseudo-glandular and/or trabecular patterns and capsular extrusion indicated the presence of pathogenic variants of ARMC5 in BMAD. The gland enlargement does not seem to be related to the increase of mitotic count or a higher proliferation index (Ki-67).

Adrenal cortical carcinoma (ACC) is an uncommon neoplasm with variable prognosis. Several histologic criteria have been identified as predictors of malignancy in adrenal cortical tumors. The Weiss score is the system most widely employed for diagnostic purposes, but also possesses prognostic value. We aim to determine the relative impact of each Weiss parameter on ACC patient survival. A multicenter retrospective analysis was conducted on a series of 79 conventional ACCs surgically treated at the Florence and Utrecht centers of the European Network for the Study of Adrenal Tumors (ENSAT). Weiss classification was recapitulated using principal component analysis (PCA). The Kaplan-Meier and Cox multivariate regression analyses were applied in order to estimate the prognostic power of Weiss versus other clinical parameters. PCA reduced the nine Weiss parameters to the best fitting 4-component model, each parameter clustering with a single component. Necrosis and venous invasion clustered together with the highest scores, thus establishing the most relevant component (Component 1) to explain Weiss distribution variability. Only Component 1 significantly predicted overall survival (OS, log-rank = 0.008) and disease-free survival (DFS, log-rank < 0.001). When considering the prognostic power of Weiss parameters, necrosis alone could independently assess OS (log-rank = 0.004) and DFS (log-rank < 0.001) at both the Kaplan-Meier and multivariate Cox regression analyses [hazard ratio (HR) = 7.8, 95% confidence interval [CI] = 1.0-63.5, p = 0.05, and HR = 12.2, 95% CI = 1.6-95.0, p = 0.017, respectively]. The presence of necrosis significantly shortened time to survival (TtS) and time to recurrence (TtR), 57.5 [31.5-103.5] vs 34 [12-78] months (p = 0.05) and 57.5 [31.5-103.5] vs 7 [1.0-31.5] months (p < 0.001), respectively. Our study suggests that, of the Weiss parameters, necrosis is the most powerful adverse factor and the best predictor of OS and DFS in ACC patients.

Adrenocortical neoplasms are rare in childhood. Their histopathological categorization into benign and malignant is often challenging, impacting further management. While the AFIP/Wieneke scoring system is widely used for the prognostic classification of these tumors, it has limitations. Few other tumor scoring systems have evolved over the past few years. These have been validated in adults but not yet in pediatric patients. We evaluated a cohort of pediatric adrenocortical neoplasms to assess the applicability of AFIP/Wieneke criteria and the recently introduced Helsinki score and reticulin algorithm in predicting clinical outcomes. A tumor was considered 'clinically aggressive' in the presence of any of the following: metastases, recurrence, progressive disease, or death due to disease. Cases without any such event were considered 'clinically good'. Event-free survival time was the duration from the date of clinical presentation to any post-operative adverse event. For overall survival analysis, the endpoint was either the last follow-up or death due to disease.Using ROC curve analysis, the obtained cut-off Helsinki score of 24 could stratify the cases into two prognostically relevant groups. Survival analysis showed significant differences in the event-free and overall survival of these two groups of patients, validating the proposed cut-off. None of the three histopathological scoring systems could predict an unfavorable outcome with 100% accuracy. All showed a sensitivity of ≥ 80%, with the reticulin algorithm achieving 100% sensitivity. The specificity and accuracy of the AFIP/Wieneke criteria were the lowest (62.5% and 73.08%, respectively). While the Helsinki score (at the cut-off score of 24) and the reticulin algorithm had similar accuracy rates (80.77%, and 80%, respectively), the specificity of the former was higher (81.25%) than the latter (68.75%). A separate analysis revealed that the Ki-67 index at a cut-off of 18% had a sensitivity of 80% and a specificity of 81.25% for predicting an unfavorable outcome.

Adrenal cortical carcinoma is an aggressive and rare malignancy of steroidogenic cells of the adrenal gland. Most adult adrenal cortical carcinomas are sporadic, but a small fraction may be associated with inherited tumor syndromes, such as Li-Fraumeni, multiple endocrine neoplasia 1, Lynch syndrome, and Beckwith-Wiedemann syndrome, as well as isolated case reports of non-syndromic manifestations occurring in the context of other pathogenic germline variants. Birt-Hogg-Dubé (BHD) is a rare autosomal dominant syndrome caused by germline pathogenic variants in the FLCN gene. BHD syndrome causes a constellation of symptoms, including cutaneous manifestations, pulmonary cysts and pneumothorax, and risk of renal tumors. With the exception of a single case of adrenal cortical carcinoma, very few reports on the occurrence of adrenal cortical neoplasia in patients with BHD syndrome have been described. However, information on variant allele fraction in the tumor was not available in the index case, which precludes any mechanism supporting loss of heterozygosity. Here we present a case of an adult-onset adrenal cortical carcinoma in a 50-year-old female, found to harbor a germline likely pathogenic variant in the FLCN gene, denoted as c.694C > T (p.Gln232Ter). Genetic testing on the tumor revealed the same FLCN variant at an allele fraction of 83%, suggesting a contributory role to the pathogenesis of the adrenal cortical carcinoma. This case further supports the expansion of the clinical presentation and tumor spectrum of BHD syndrome and the need to consider germline FLCN testing in the clinical genetic workup of patients with adrenal cortical carcinomas.

Although pediatric thyroid tumors have many similarities to those occurring in adults, significant differences are also recognized. For example, although thyroid nodules in children are much less common than in adults, a higher percentage is malignant. Moreover, while pediatric papillary thyroid carcinoma (PTC) is associated with more advanced disease, death due to disease in children and adolescents is very rare, even when distant metastases are present. Some subtypes of thyroid carcinoma, like diffuse sclerosing variant, are especially common in children and adolescents. Moreover, certain histologic findings, such as a tall cell morphology or increased mitotic activity, may not carry the same prognostic significance in children as in adults. Recent studies exploring the molecular underpinnings of pediatric thyroid carcinoma indicate that while driver alterations of thyroid tumorigenesis in children and adults are essentially the same, they occur at very different frequencies, with translocation-associated tumors (most commonly harboring RET and NTRK fusions) comprising a sizable and distinct group of pediatric PTC. DICER1 mutations, an infrequent mutation in adult thyroid tumors, are relatively frequent in pediatric encapsulated follicular-patterned thyroid tumors (with or without invasion or nuclear features of PTC). Additionally, tumor predisposition syndromes (most notably DICER1 syndrome and PTEN hamartoma tumor syndromes such as Cowden syndrome) should be considered in children with thyroid tumors, especially follicular-patterned thyroid tumors and poorly differentiated thyroid carcinoma. This review will explore the current state of knowledge of thyroid nodules and carcinomas in children and adolescents.

Mucoepidermoid carcinoma (MEC) and sclerosing MEC with eosinophilia (SMECE) are rare primary thyroid carcinomas. In this study, we aimed to present our multicenter series of MEC and SMECE and integrated our data with published literature to further investigate the clinicopathological characteristics and prognoses of these tumors. We found 2 MECs and 4 SMECEs in our multicenter archives. We performed fluorescence in situ hybridization (FISH) to determine the MAML2 gene rearrangement. We screened for mutations in BRAF, TERT promoter, and RAS mutations using Sanger sequencing and digital polymerase chain reaction. Histopathologically, MECs and SMECEs were composed of two main cell types including epidermoid and mucin-secreting cells, arranged in cords, nests, and tubules. SMECEs were characterized by a densely sclerotic stroma with abundant eosinophils. We did not detect any MAML2 fusion in any of our cases. Two MEC cases harbored concomitant BRAF p.V600E and TERT C228T mutations. RAS mutations were absent in all cases. Concurrent foci of another thyroid malignancy were more commonly seen in MECs (p < 0.001), whereas SMECEs were associated with chronic lymphocytic thyroiditis (p < 0.001). MECs and SMECEs had equivalent recurrence-free survival (RFS) but MECs conferred significantly dismal disease-specific survival (DSS) as compared to SMECEs (p = 0.007). In conclusion, MECs and SMECEs not only shared some similarities but also demonstrated differences in clinicopathological characteristics, prognoses, and molecular profiles. SMECEs had a superior DSS in comparison to MECs, suggesting that they are low-grade cancers. This could help clinicians better evaluate patient outcomes and decide appropriate treatment plans.

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare neuroendocrine tumors originating from chromaffin cells. Even though only 10-15% of the tumors metastasize, all PPGLs are considered potentially malignant. Topoisomerase 2A (TOP2A) is a protein involved in cell proliferation and has been found to be over-expressed in metastatic PPGL. To provide support whether TOP2A could serve as a prognostic marker, 88 PPGLs (of which 8 metastatic/relapsing) and 10 normal adrenal gland samples were assessed for TOP2A mRNA expression using quantitative real-time PCR (qRT-PCR) and TOP2A immunohistochemistry. Comparisons to clinical parameters connected to metastatic behavior were made, and The Cancer Genome Atlas was used for validation of the results. A significant association between high TOP2A mRNA expression in primary PPGL and subsequent metastatic events (p = 0.008) was found, as well as to specific histological features and clinical parameters connected to metastatic behavior and mutations in SDHB. TOP2A immunoreactivity was calculated as an index of positive nuclei divided by the total amount of nuclei, and this index associated with TOP2A mRNA levels (p = 0.023) as well as the Ki-67 labeling index (p = 0.001). To conclude, TOP2A is a potential prognostic marker as it is frequently elevated in PPGL displaying subsequent metastatic disease, and future studies in larger cohorts are warranted to determine if a TOP2A index as assessed by immunohistochemistry could be a marker of poor outcome. Additionally, elevated levels of TOP2A could indicate a potential actionable event, and future studies with topoisomerase inhibitors would be of interest.