The Reactivity of Hydroxyl Radicals toward Boric Acid as a Function of pH.

Boric acid and its counter-base, borate, are a commonly used buffer pair in many systems where hydroxyl radicals are generated. Boric acid is also used in light water-cooled nuclear reactors to control the excess reactivity of the nuclear fuel. Hydroxyl radicals are generated within the cooling water of the reactor because of intense radiation. The reactivity of the hydroxyl radical toward boric acid has previously been studied, but to the best of our knowledge, only upper limits of the rate constants are available in the literature. In this study, the rate constants for the reaction between the hydroxyl radical and boric acid and its counter-base including several polyborates that form at high boron concentration are determined. The rate constants were determined from competition kinetics using steady-state γ radiolysis and coumarin-3-carboxylic acid as the competing reactant. By varying the pH and accounting for boron speciation, it was possible to determine the rate constant for the different boron species using multilinear regression. The rate constants for boric acid and the counter-base were determined to be 3.6 × 104 and 1.1 × 106 M-1·s-1, respectively, which is very close to the previously determined upper limits of the rate constants. For the polyborate species diborate and tetraborate, the rate constant was determined to be 6.4 × 106 and 6.8 × 106 M-1·s-1, respectively.

Primary Epithelioid Angiosarcoma of the Submandibular Gland-A Case Report with Histology-Cytology Correlation and Comprehensive Molecular Analysis.

BACKGROUND: Angiosarcoma is a sarcoma that occurs in a range of tissue types, and only rarely in the salivary glands, showing a predilection for the parotid glands of older patients. Preoperative diagnosis may be challenging, especially on cytology, with significant morphological overlap with high-grade primary salivary gland carcinomas. The molecular alterations of this rare salivary gland neoplasm are also not well-characterized. METHODS AND RESULTS: We present a case of right submandibular gland swelling in a 73-year-old male. On fine needle aspiration, including immunohistochemical stains on cell block, the tumor was initially diagnosed as poorly differentiated carcinoma. Resection of the submandibular gland revealed epithelioid angiosarcoma. We performed molecular work-up of the tumor, utilizing targeted next-generation sequencing, DNA methylation profiling and fluorescence in-situ hybridization. Histopathologic assessment revealed an infiltrative tumor comprising solid sheets of epithelioid cells. The tumor cells formed haphazardly anastomosing vascular channels with intracytoplasmic lumina containing red blood cells. On immunohistochemistry, the tumor cells were positive for CD31, CD34 and ERG. Approximately 40% of the tumor cells showed nuclear expression of GATA3. A pathogenic TP53 R267W mutation was detected on next-generation sequencing. DNA methylation analysis did not cluster the tumor with any known sarcoma type. Copy number analysis showed possible MYC amplification and CDKN2A losses, although only the latter was confirmed on fluorescence in-situ hybridization. CONCLUSION: Epithelioid angiosarcoma is an important differential diagnosis to high-grade salivary gland carcinoma. In particular, GATA3 expression may be encountered in both angiosarcoma and high-grade salivary gland carcinomas and cause diagnostic confusion. Identification of TP53 mutations and CDKN2A losses suggest shared oncogenic pathways with soft tissue angiosarcomas, and should be further investigated.

Ocular Crystal-Storing Histiocytosis with Co-existing MALT Lymphoma-A Rare Case with Cytologic and Heretofore Not Reported Findings on Frozen Section.

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare disorder which most commonly occurs in the setting of concurrent lymphoproliferative disease. Morphologically, it consists of aggregates of histiocytes containing eosinophilic crystalline material, which in most cases is composed of aggregated abnormal light chains. METHODS: Using histomorphology, immunohistochemistry and in situ hybridization, the authors characterize a rare case of orbital CSH associated with extranodal marginal zone (MALT) lymphoma and report for the first time the frozen section features of CSH. RESULTS: The frozen section featured plump histiocytes with ample weakly basophilic to grayish cytoplasm with a microvacuolated appearance and focal stippling. These features stand in contrast with the formalin-fixed, paraffin embedded histomorphological appearance of aggregates of plump histiocytes with densely eosinophilic crystalline cytoplasmic material. CONCLUSION: CSH is a challenging diagnosis to make on frozen section. The artifacts that preclude its recognition, as well as differential diagnoses of this entity in the head and neck are discussed.

Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract.

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

The Challenge of "Monomorphic" Mucoepidermoid Carcinoma-Report of a Rare Case with Pure Spindle-Clear Cell Morphology.

BACKGROUND: Mucoepidermoid carcinoma is a malignant salivary gland tumor which, in most cases, is composed of variable proportions of mucous, epidermoid, and intermediate cells. METHODS: We report a case of parapharyngeal mucoepidermoid carcinoma with highly unusual ("monomorphic") light microscopic features as well as atypical immunohistochemical properties. Molecular analysis was performed using the TruSight RNA fusion panel. RESULTS: The tumor featured heretofore undescribed histopathological features: sheets and nests composed of monomorphic neoplastic (plump spindle to epithelioid) cells with no mucous, intermediate, glandular/columnar, or any other cell type identified. The neoplastic cells displayed variable clear cell change and only expressed cytokeratin 7. Despite this non-classical morphology, the presence of the classical CRTC1::MAML2 fusion was demonstrated. CONCLUSIONS: Mucoepidermoid carcinoma featuring a uniform ("monomorphic") population of neoplastic cells is a novel observation. A confident diagnosis of mucoepidermoid carcinoma can be made upon detection of the CRTC1/3::MAML2 fusion. Our case increases the spectrum of histopathological appearances that mucoepidermoid carcinoma may display.

Oncocytic low-grade myoepithelial carcinoma ex pleomorphic adenoma - A rare case illustrating key learning points.

BACKGROUND: Oncocytic myoepithelial carcinoma ex pleomorphic adenoma neoplastic is a rare neoplastic event and may not display overt malignant radiological features. METHODS: Using routine histopathology and immunohistochemistry, we characterize a case of low-grade oncocytic carcinoma ex pleomorphic adenoma. RESULTS: The tumor arose in the left parotid gland in a 59 year old female. Computed tomography (CT) imaging demonstrated a well-defined, lobulated, enhancing lesion with relative central stellate hypoenhancement. Histologically, the tumor displayed a multi-nodular, non-destructive, invasive pattern, low mitotic activity (one mitotic figure per 10 high power fields) and a small remnant focus of pleomorphic adenoma. The neoplastic cells showed significant expression of cytokeratin 5/6, S-100 protein, smooth muscle actin and p63. CONCLUSION: Low-grade oncocytic carcinoma ex pleomorphic adenoma is a challenging histopathological diagnosis which can be established with use of immunohistochemistry, generous tumor sampling and recognition of the multi-nodular, non-destructive, pattern of invasion. In the absence of clear-cut tumor encroachment into external structures, its malignant nature may not be easily identified on pre-operative imaging.

Sclerosing polycystic adenoma - A review.

This review summarizes the current state of knowledge on sclerosing polycystic adenoma, including epidemiological/clinical, histopathological/cytopathological, ultrastructural, immunohistochemical and etiopathogenetic/molecular genetic aspects. Differential diagnostic issues are briefly discussed.

Sclerosing microcystic adenocarcinoma of the parotid gland - The first recorded case with histo-cytopathologic correlation and a brief review of the literature.

We present a case of a 1.0 cm primary tumor of the left parotid gland that meets the histological criteria for the recently described entity sclerosing microcystic adenocarcinoma. The patient was a 73-year-old man with a concurrent tonsillar squamous cell carcinoma, and a history of nasopharyngeal carcinoma treated with radiotherapy 23 years prior. Fine needle aspiration cytology demonstrated low-grade biphasic basaloid neoplastic cells arranged in branching sheets and clusters with minimal nuclear pleomorphism. A biphasic appearance was apparent and some of the cell clusters were bordered by a layer of flattened cells with ovoid bland nuclei. On histology, the tumor comprised small bilayered infiltrative tubules, nests, cords, and microcysts. On immunohistochemistry, EMA, SOX-10, P63, and S-100 protein highlighted a dual cell population of luminal and abluminal cells. The cells were negative for CD117, and the Ki-67 proliferation index was low (<5%).

Epithelioid Sarcoma of the External Auditory Canal: An Uncommon Tumor at an Unusual Site and a Brief Overview of the Literature.

We present a case (41 years old pregnant female) with epithelioid sarcoma arising in the left external auditory canal. On immunohistochemistry, the tumor cell diffusely expressed cytokeratins and showed patchy expression of ERG and CD34. The neoplastic cells demonstrated uniform loss of INI1-expression. Epithelioid sarcoma arising in the external auditory canal is rare. Awareness that ES may rarely arise at unusual sites is of critical importance in order to apply a broad enough panel in the immunohistochemical study, so a misdiagnosis of carcinoma can be avoided.

Ectopic Cervical Thyroid Tissue Affected by Fibrosing Hashimoto's Thyroiditis Mimicking Multifocal Metastatic Papillary Thyroid Carcinoma-A Hard Lesson Learnt from an Unusual Case.

We describe a case of ectopic cervical thyroid tissue which was involved by fibrosing Hashimoto's thyroiditis and which mimicked metastatic papillary thyroid carcinoma both on fine needle aspiration cytology and biopsy. The patient underwent total thyroidectomy which revealed fibrosing Hashimoto's thyroiditis, but no carcinoma. The entire thyroidectomy specimen was submitted for histopathological assessment. Even in the resected thyroidectomy specimen, there were cytological changes that were strongly reminiscent of papillary thyroid carcinoma. However, interpreted in the correct clinico-pathological context, these cytological alterations were deemed to be reactive secondary to the fibro-inflammatory process.

Adenoid cystic carcinoma with dedifferentiation/expansion of the luminal cell component and preserved biphasic morphology - Early high-grade transformation.

We present two patients (29 and 67 years) with histomorphologic and immunohistochemical evidence of early high-grade transformation of adenoid cystic carcinoma in the nasal cavity and floor of mouth, respectively. The component of early high-grade transformation was characterized by 1) selective expansion of the luminal (CK7+, c-kit+, p63-) cell component with severe cytologic atypia and significantly increased Ki-67 proliferation index, and 2) retained albeit attenuated abluminal (CK7-, c-kit-, p63+) cells, surrounding nests of high-grade luminal cells.

Typical and atypical carcinoid tumors of the lung: a clinicopathological correlation of 783 cases with emphasis on histological features.

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcomes. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2 mm2, necrosis, lymphatic invasion, and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlated with clinical outcomes. Based on our analysis, we consider that the separation of low- and intermediate-grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of overgrading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcomes.

Nasal Cavity Metastasis From Colorectal Cancer Represents End-Stage Disease and Should Be Palliated.

Nasal metastases from colorectal cancer is rare. The presentation of nasal metastases is often very similar to primary nasal sinus adenocarcinoma. A high index of suspicion is required, especially in patients who have had a previous history of colorectal carcinoma. Histology is ultimately required for diagnosis. We describe 2 cases of nasal metastases from colorectal carcinoma, and discuss the presentation, diagnosis and management of the case. Such metastatic disease ultimately represents end-stage malignancy, and patients should be palliated.

Cervical Myxoid Solitary Fibrous Tumor: Report of an Unusual Variant and a Brief Overview of the Literature.

We present a 49 year old female with a diagnostically challenging myxoid solitary fibrous tumor arising in the soft tissue of the neck. The tumor was diffusely positive for CD34 and STAT6 on immunohistochemistry.

Lipomatous basal cell adenoma (Basal cell lipoadenoma) - Report of the first two cases.

We present, to the best of our knowledge, the first two cases (60 year old female and 71 year old male) of basal cell adenoma with significant adipocytic components and suggest the term "lipomatous basal cell adenoma" for these lesions. Both tumors presented as slow growing nodules in the parotid gland. The two cases represent different points on a histopathological spectrum with one case being extremely well differentiated with distinct spiradenoma-like histological features; distinct bilayering, duct formation with secretory material and very low proliferative activity and the other case displaying more primitive cytological features composed of a predominant uniform, (p63-positive; CK 7-negative) basaloid, abluminal cell type, high proliferative activity and only scattered true ducts composed of (CK7-positive, p63-negative) luminal cells.

Frequent overexpression of klotho in fusion-negative phosphaturic mesenchymal tumors with tumorigenic implications.

Phosphaturic mesenchymal tumors (PMT) are tumors that cause hypophosphatemia/osteomalacia chiefly by secreting FGF23. We have identified FN1-FGFR1/FGF1 fusion genes in nearly half of PMT, suggesting a central role of FGFR1 pathways in the pathogenesis of PMT. Tumorigenic drivers are unknown for tumors where previous study detected neither fusion, including many in bone, where FISH failed because of tissue decalcification. To identify alternative fusions in PMT without known fusions, as well as to validate the positive FISH results and characterize the fusion junctions, 34 PMT were studied, including 12 with known FN1-FGFR1 fusion by FISH (Group A), 2 with FN1-FGF1 (B), 12 with neither fusion (C), and 8 with previous acid-based decalcification and hence unknown fusion status (D). In total, 23 archival samples were subjected to anchored multiplex PCR-based RNA-sequencing (AMP-seq) with primers targeting FN1, genes encoding the FGF/FGFR families, and KL (α-Klotho); five Group C cases were also studied with whole-transcriptomic and exome-captured RNA sequencing, respectively. The AMP-seq results were consistent with previous FISH and/or transcriptomic sequencing data, except in one old Group A sample. One case had a novel FGFR1 exon 9 breakpoint, confirmed by genomic DNA sequencing. One Group D bone tumor was found to harbor FN1-FGF1. All 3 RNA-sequencing platforms failed to identify convincing fusion genes in Group C (N = 10), which instead expressed significantly higher levels of either KL or KLB. This result was further confirmed with KL and KLB RNA CISH semi-quantification (RNAscope). Our results demonstrated the utility of AMP-seq, which was compromised by decalcification and prolonged archiving. Of potential importance, fusion-negative PMT frequently overexpressed α-Klotho (or instead ß-Klotho less commonly), whose role as an obligatory co-receptor for FGF23-FGFR1 binding suggests its aberrant expression in osteocytes/osteoblasts might result in an FGF23-FGFR1 autocrine loop that in turn drives the overexpression of FGF23 and tumorigenesis through activated FGFR pathways.