Thyroid tumors usually present as masses in the thyroid gland. While the majority of these tumors represent neoplasms of thyroid tissues, mainly of follicular epithelial cell differentiation, the ...differential diagnosis includes other lesions, such as C cell neoplasms (medullary thyroid carcinoma), intrathyroidal parathyroid, or thymic tumors, soft tissue tumors, and hematologic neoplasms as well as metastatic malignancies. Rare tumors are of salivary gland types. This case illustrates an unusual tumor of salivary gland type, an intrathyroidal mammary analog secretory carcinoma (MASC). The pathogenesis, diagnostic pitfalls, and therapeutic implications of this unusual tumor are discussed.
Background:
Parathyroid carcinoma is rare, representing <1% of primary hyperparathyroidism cases.
Methods:
Retrospective data of patients referred for evaluation of parathyroid disease between 2001 ...and 2018 were reviewed. The goal was to describe the clinical presentation, histopathologic characteristics, and treatment outcomes of parathyroid carcinoma.
Results:
We identified 8 cases of parathyroid carcinoma from the outpatient practice of a quaternary care Endocrine Oncology practice in Toronto, Canada. The clinical presentation was as follows: 5/8 cases (62.5%) of symptomatic hypercalcemia and 3/8 cases (37.5%) of a suspicious thyroid nodule. Hypercalcemia was evident in all 7 cases with pre-operative calcium measurements. Histopathologic features included: vascular invasion in 7/8 cases (87.5%) and immunohistochemical loss of either parafibromin, retinoblastoma, or p27 in all 8 cases. Additional treatment included: external beam radiotherapy in 5/8 cases (62.5%), chemotherapy for 2/8 patients (25%), and additional surgery for 3/8 patients (37.5%). Only 2 patients (25%) had long-term remission following surgical treatment, and the others had either persistent (3 patients) or recurrent disease (3 patients). Five patients developed metastatic disease, all involving lung. In one of two patients treated with Sorafenib there was evidence of regression of lung metastases. One patient died of disease progression.
Conclusion:
In this series of patients with parathyroid carcinoma largely presenting with symptomatic hypercalcemia and angioinvasive disease, only a minority achieved a durable remission. Lung was the most common site of distant metastasis. Surgery led to remission in two cases, but none of the six patients with persistent or recurrent disease ultimately achieved disease remission.
This morphological and immunohistochemical study demonstrates that tumors currently known as “middle ear adenomas” are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of ...cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders.
Despite the established role of Ki67 labeling index in prognostic stratification of adrenocortical carcinomas and its recent integration into treatment flow charts, the reproducibility of the ...assessment method has not been determined. The aim of this study was to investigate interobserver variability among endocrine pathologists using a web-based virtual microscopy approach. Ki67-stained slides of 76 adrenocortical carcinomas were analyzed independently by 14 observers, each according to their method of preference including eyeballing, formal manual counting, and digital image analysis. The interobserver variation was statistically significant (P<0.001) in the absence of any correlation between the various methods. Subsequently, 61 static images were distributed among 15 observers who were instructed to follow a category-based scoring approach. Low levels of interobserver (F=6.99; Fcrit=1.70; P<0.001) as well as intraobserver concordance (n=11; Cohen κ ranging from -0.057 to 0.361) were detected. To improve harmonization of Ki67 analysis, we tested the utility of an open-source Galaxy virtual machine application, namely Automated Selection of Hotspots, in 61 virtual slides. The software-provided Ki67 values were validated by digital image analysis in identical images, displaying a strong correlation of 0.96 (P<0.0001) and dividing the cases into 3 classes (cutoffs of 0%-15%-30% and/or 0%-10%-20%) with significantly different overall survivals (P<0.05). We conclude that current practices in Ki67 scoring assessment vary greatly, and interobserver variation sets particular limitations to its clinical utility, especially around clinically relevant cutoff values. Novel digital microscopy-enabled methods could provide critical aid in reducing variation, increasing reproducibility, and improving reliability in the clinical setting.
The hypothalamus is the site of synthesis and secretion of a number of endocrine peptides that are involved in the regulation of hormonal activity of the pituitary and other endocrine targets. Tumors ...of the hypothalamus have been recognized to have both structural and functional effects including hormone hypersecretion. The classification of these tumors has advanced over the last few years, and biomarkers are now available to classify these tumors and provide accurate structure–function correlations. This review provides an overview of tumors in this region that is critical to metabolic homeostasis with a focus on advances in the diagnosis of gangliocytomas, neurocytomas, and pituicytomas that are unique to this region.
Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant ...is identified in 95-100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10-55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL variant negative cases.
Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor ...prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (
n
= 42), adrenal cortical adenoma (ACA;
n
= 50), and normal adrenal cortical tissue samples (
n
= 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (
p
< 0.001 and
p
= 0.014, respectively) or normal adrenal cortical tissue samples (
p
< 0.001 and
p
< 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (
p
< 0.001 and
p
< 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (
p
= 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (
p
= 0.003) or normal adrenal cortical tissue samples (
p
= 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (
p
< 0.001 and
p
= 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.
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