An Atypical Cause of Hoarseness in a Patient With Thyroid Nodules.

Hoarseness due to vocal fold paresis (VFP) has a multitude of etiologies including systemic lupus erythematosus (SLE). During a clinical evaluation of a 58-year-old woman with long-standing hoarseness, an incidental finding of thyroid nodules was found to have VFP. Direct laryngoscopy and vocal fold biopsy confirmed the source was an inflammatory process involving the cricoarytenoid joint of the right hemilarynx. A presumptive diagnosis of SLE was made 3 years before meeting the clinical criteria of overt SLE. The VFP debut of SLE is extremely rare, and a literature review includes a handful of case reports (4 of a total of 37) since 1959. Only partial recovery of laryngeal function using glucocorticoids and Plaquenil was accomplished in the current case.

Rosai-Dorfman Disease of the Rectum: Newly Identified Genetic Point Mutations and Robotic Resection.

Rosai-Dorfman disease (RDD) is a rare disease characterized by histiocytic proliferation which typically presents as massive, painless, cervical lymphadenopathy in children or young adults. GI involvement is exceedingly rare with only 20 documented cases to date. Of those 20 cases, only 3 cases have involved the rectum. Here, we present 2 cases of rectal RDD with attention paid to the diagnostic and technical challenges presented by this disease. When presenting as a perirectal mass, RDD can be mistaken for other lesions to include malignancy, leading to surgical removal. We present a video of a robotic low-anterior resection with intracorporeal anastomosis in order to remove a pelvic mass involving the rectum, initially considered to be a stromal tumor. In addition, we describe a copy number variation in AKT and 3 point mutations detected by next generation sequencing, which had not been previously reported in association with this disease.

Sarcoidosis Presenting as Dorsal Wrist Mass: A Case Report.

Patients with sarcoidosis have an indolent course in which the disease is not detected unless seemingly benign symptoms appear. Such was the case in a 42-year-old man who was referred to the orthopedic service for evaluation of a slowly enlarging mass over the left wrist without prior history of trauma. In this article, we will review the symptoms and histopathology of sarcoidosis with a particular focus on orthopedic manifestations of the disease. We believe that clinicians should be aware of these associations so that patients can be diagnosed and treated accordingly.

The distribution of parotid gland neoplasms in a veteran population.

OBJECTIVE: Salivary gland tumors account for 6%-8% of head and neck neoplasms with the parotid gland as the most common primary site. Pleomorphic adenomas (PA) are considered the most common benign parotid gland neoplasms, followed by Warthin tumors (WT). The goal of this study was to investigate the distribution of parotid gland neoplasms among a United States veteran population. DESIGN: Retrospective chart review. SETTING: Washington DC Veterans Affairs Medical Center. PARTICIPANTS: Veterans who underwent fine needle aspiration (FNA) for a parotid gland mass from 2000 to 2018 were included. Medical records were reviewed for gender, age, tobacco use, surgery date, and pathology results. MAIN OUTCOME MEASURES: Changes in the distribution of parotid neoplasms and tobacco use over an 18-year period. RESULTS: Of 141 patients with parotid gland masses, 86.5% (n = 122) were benign, 9.9% (n = 14) were malignant, and 3.5% (n = 5) were indeterminate. Of benign tumors, WT accounted for the majority at 51.6%, followed by PA at 40.2%. When stratified by decade (2000-2009 and 2010-2018), the proportion of WT compared to all other benign and malignant neoplasms increased from 31.6% to 53.6%, whereas the proportion of PA decreased from 36.8% to 33.3%. The rate of tobacco use was unchanged at approximately 32.0% among our cohort from 2000 to 2018. CONCLUSION: Among our cohort of veteran patients, WT was the most common benign parotid tumor and has increased in incidence over the last two decades despite an unchanged smoking rate.

Approach to Cystic Lesions in the Abdomen and Pelvis, with Radiologic-Pathologic Correlation.

Cystic lesions found in and around the peritoneal cavity can often be challenging to diagnose owing to significant overlap in imaging appearance between the different entities. When the cystic lesion can be recognized to arise from one of the solid abdominal organs, the differential considerations can be more straightforward; however, many cystic lesions, particularly when large, cannot be clearly associated with one of the solid organs. Cystic lesions arising from the mesentery and peritoneum are less commonly encountered and can be caused by relatively rare entities or by a variant appearance of less-rare entities. The authors provide an overview of the classification of cystic and cystic-appearing lesions and the basic imaging principles in evaluating them, followed by a summary of the clinical, radiologic, and pathologic features of various cystic and cystic-appearing lesions found in and around the peritoneal cavity, organized by site of origin. Emphasis is given to lesions arising from the mesentery, peritoneum, or gastrointestinal tract. Cystic lesions arising from the liver, spleen, gallbladder, pancreas, urachus, adnexa, or soft tissue are briefly discussed and illustrated with cases to demonstrate the overlap in imaging appearance with mesenteric and peritoneal cystic lesions. When approaching a cystic lesion, the key imaging features to assess include cyst content, locularity, wall thickness, and presence of internal septa, solid components, calcifications, or any associated enhancement. While definitive diagnosis is not always possible with imaging, careful assessment of the imaging appearance, location, and relationship to adjacent structures can help narrow the differential diagnosis. Online supplemental material is available for this article. ©RSNA, 2021.

Inclusion of an E7 DNA Amplification Test Improves the Robustness of Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma Diagnosis.

BACKGROUND: The rise in human papillomavirus (HPV) infection rates over the last few decades in the USA has contributed to a significant increase in the overall incidence of patients diagnosed with squamous cell carcinoma of the head and neck. These head and neck carcinomas develop in the oropharynx, with more than 90% of them caused by infection with high-risk HPV type 16. Patients diagnosed with HPV-induced oropharyngeal squamous cell carcinomas (OPSCCs) have a better prognosis and treatment response than those diagnosed with head and neck cancers caused by alcohol consumption and tobacco use. To identify patients with HPV-positive OPSCC, new guidelines recommend positive staining of oropharyngeal tissues for p16 INK4a (p16) by immunohistochemistry (IHC). Herein we discuss the testing algorithm that was adopted to address discrepant results between p16 IHC and a DNA in situ hybridization (ISH) test used routinely to diagnose HPV-positive OPSCC patients. METHODS: A DNA polymerase chain reaction (PCR) test that amplifies HPV16 and HPV18 E7 was developed to aid in the diagnosis of HPV-positive OPSCC in a subset of patients. Specimens from these patients stained positive for p16 by an IHC test, but negative for high-risk HPV by a commercial DNA ISH test. Moreover, these results did not match the histopathological characteristics of the specimens, nor the clinical presentations of the patients. RESULTS: Of 21 patients' specimens that were tested for p16 by IHC, 11 specimens showed concordant results with the high-risk HPV 16/18 DNA ISH test. Whereas, in eight p16 IHC positive specimens, HPV viral DNA was not detected by HPV16/18 DNA ISH, and two specimens were not tested by DNA ISH. When these eight p16 IHC positive specimens with discrepant p16 IHC and DNA ISH results were further tested by DNA PCR, six specimens showed concordance with p16 IHC with positive results for HPV16 E7, while two specimens were negative for HPV16 E7 by DNA PCR. All tested specimens were negative for HPV18 E7 by DNA PCR. Thus, the addition of the HPV16 and HPV18 E7 DNA PCR test identified a significant number of false negative test results by the HPV16/18 DNA ISH test and likely several false positive results by p16 IHC. CONCLUSIONS: Inclusion of an HPV16 E7 DNA PCR test improved the robustness of HPV-associated OPSCC diagnosis in patients with discrepant results from p16 IHC staining and a DNA ISH test, and identified patients for proper management with less misclassification.

Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer.

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.

Endothelium-Derived Factors Influence Differentiation of Fat-Derived Stromal Cells Post-Exercise in Subjects with Prediabetes.

Purpose: We investigated the effect of aerobic and resistance exercise on abdominal subcutaneous fat-derived stromal cells in middle-aged subjects with prediabetes, pre- and post-exercise to establish molecular mechanisms that drive the effect of exercise. Methods: Five subjects, aged between 40 and 60 years with a body mass index between 25 and 39.9 kg/m2 and with prediabetes, were enrolled in a 12-week exercise intervention program. Biophysical parameters were assessed pre- and post-exercise. Stromal cells were obtained from subcutaneous abdominal fat and cultured for 2-3 weeks. The stromal cells were then analyzed for mRNA analysis pre- and post-exercise. This was followed up with in vitro experiments where commercially obtained human fat-derived mesenchymal stromal cells (MSCs) were exposed to adipogenic media, and conditioned media from human endothelial conditioned media (ECM) cells were added to note if ECM addition altered adipogenesis. Subsequently, MSC differentiation was monitored by reverse transcription-polymerase chain reaction (RT-PCR). Results: Post-exercise, subjects' cardiometabolic parameters improved. MSC obtained at post-exercise phase, from subcutaneous fat biopsies, on RT-PCR analysis, showed upregulation of antioxidant, mitochondrial, glucose transporter, and genes associated with osteogenesis compared with pre-exercise MSC mRNA. A concomitant increase in plasma osteocalcin levels was also noted post-exercise. In vitro, MSCs exposed to adipogenic differentiation media with the addition of ECM showed a significant reduction in expression of adipogenic marker genes and instead showed upregulation of genes associated with osteogenic differentiation. Conclusions: Exercise appears to prevent adipogenic differentiation of fat-derived stromal cells and promote osteogenic differentiation, in prediabetic middle-aged subjects. Interestingly, the addition of endothelium-derived factors to adipogenic media also appears to prevent adipogenic differentiation of commercially obtained fat-derived stromal cells and promotes osteogenic differentiation. Both in vivo and in vitro findings emphasize the paracrine effect of endothelium-derived factors on fat differentiation.

Evidence for a regulated Ca2+ entry in proximal tubular cells and its implication in calcium stone formation.

Calcium phosphate (CaP) crystals, which begin to form in the early segments of the loop of Henle (LOH), are known to act as precursors for calcium stone formation. The proximal tubule (PT), which is just upstream of the LOH and is a major site for Ca2+ reabsorption, could be a regulator of such CaP crystal formation. However, PT Ca2+ reabsorption is mostly described as being paracellular. Here, we show the existence of a regulated transcellular Ca2+ entry pathway in luminal membrane PT cells induced by Ca2+-sensing receptor (CSR, also known as CASR)-mediated activation of transient receptor potential canonical 3 (TRPC3) channels. In support of this idea, we found that both CSR and TRPC3 are physically and functionally coupled at the luminal membrane of PT cells. More importantly, TRPC3-deficient mice presented with a deficiency in PT Ca2+ entry/transport, elevated urinary [Ca2+], microcalcifications in LOH and urine microcrystals formations. Taken together, these data suggest that a signaling complex comprising CSR and TRPC3 exists in the PT and can mediate transcellular Ca2+ transport, which could be critical in maintaining the PT luminal [Ca2+] to mitigate formation of the CaP crystals in LOH and subsequent formation of calcium stones.

Nonepithelial Neoplasms of the Pancreas, Part 2: Malignant Tumors and Tumors of Uncertain Malignant Potential From the Radiologic Pathology Archives.

Almost all neoplasms of the pancreas are derived from pancreatic epithelial components, including the most common pancreatic mass, primary pancreatic ductal adenocarcinoma (PDAC). Nonepithelial neoplasms comprise only 1%-2% of all pancreatic neoplasms. Although some may arise directly from intrapancreatic elements, many originate from mesenchymal, hematopoietic, or neural elements in the retroperitoneal peripancreatic space and grow into the pancreas. Once these tumors reach a certain size, it can be challenging to identify their origin. Because these manifest at imaging as intrapancreatic masses, awareness of the existence and characteristic features of these nonepithelial neoplasms is crucial for the practicing radiologist in differentiating these tumors from primary epithelial pancreatic tumors, an important distinction given the vastly different management and prognosis. In part 1 of this article, the authors reviewed benign nonepithelial neoplasms of the pancreas. This article focuses on malignant nonepithelial neoplasms and those of uncertain malignant potential that can be seen in the pancreas. The most common malignant or potentially malignant nonepithelial pancreatic tumors are of mesenchymal origin and include soft-tissue sarcomas, solitary fibrous tumor, and inflammatory myofibroblastic tumor. These tumors commonly manifest as large heterogeneous masses, often containing areas of necrosis and hemorrhage. The clinical features associated with these tumors and the imaging characteristics including enhancement patterns and the presence of fat or calcification help distinguish these tumors from PDAC. Hematopoietic tumors, including lymphoma and extramedullary plasmacytoma, can manifest as isolated pancreatic involvement or secondarily involve the pancreas as widespread disease. Hyperenhancing paragangliomas or hypervascular metastatic disease can mimic primary pancreatic neuroendocrine tumors or vascular anomalies.

Microcalcifications in stone-obstructed human submandibular gland are associated with apoptosis and cell proliferation.

OBJECTIVE: Human submandibular gland (SMG) stones are associated with inflammation, fibrosis and microcalcifications in the surrounding tissues. However, there is little information about the accompanying cell injury-repair process, apoptosis, and cell proliferation. The purpose of this study was to investigate such an association and its clinical significance. DESIGN OF STUDY: Mid-gland paraffin sections of human SMGs ("stone glands") and normal SMGs ("non-stone glands") were subjected to stains for general histology (hematoxylin and eosin), fibrosis (Masson's trichrome), and calcification (alizarin red) and to immunohistochemistry for proliferative activity (Ki-67), and apoptosis (Caspase-3). Tissues were assessed for areas of inflammation, calcium deposition, and fibrosis, and for cycling and apoptotic cells. RESULTS: Acini were atrophic and proportionately fewer in lobules with fibrosis in stone glands. Additionally, stone glands had intraluminal calcifications (microliths) in scattered excretory and striated ducts and blood vessel walls. Areas of inflammation and fibrosis were small and uncommon, and calcifications were not seen in non-stone glands. Proliferating and apoptotic cells were common in the main duct of stone glands where ciliated and mucous cell hyperplasia and stratified squamous metaplasia had occurred, uncommon in the main duct of non-stone glands, and uncommon in all other parenchymal elements of both stone and non-stone glands. CONCLUSION: Stone obstruction in the main excretory ducts of SMG resulted in progressive depletion of acini from proximal to distal lobules via calcification, inflammation, fibrosis, and parenchymal cell atrophy, apoptosis and proliferation. Interlobular duct microliths contributed to this depletion by further provoking intralobular inflammation, fibrosis, and acinar atrophy.

The minimum volume of pleural fluid required to diagnose malignant pleural effusion: A retrospective study.

BACKGROUND: Pleural fluid cytology is a quick and accurate method to diagnose malignant pleural effusions. The optimal volume of fluid for cytological analysis has not yet been identified, and clinical recommendation based on some published clinical experiences has been to send large volumes of fluid for cytological analysis. A quality improvement initiative at our institution was conducted to determine the volume of fluid sufficient for a diagnosis of malignant pleural effusion. MATERIALS AND METHODS: The study was approved by the Institutional Review Board. All pleural fluid specimens that were divided into three volumes (25 mL, 50 mL, and 150 mL) and sent for cytological examination were reviewed. RESULTS: A total of 74 samples from 60 individual patients were evaluable. Thirty-six patients (60%) had a previous diagnosis of malignancy. Of the 74 specimens, 26 (35.1%) were positive for malignancy. The detection rate for malignant pleural effusion by cytology for 25 mL, 50 mL, and 150 mL were 88.5%, 96.2%, and 100.0%, respectively (P = 0.16). Two specimens that were negative in the 25 mL samples turned out to be positive in the 50 mL and 150 mL samples. One specimen was negative in the 25 mL and 50 mL samples but positive in the 150 mL sample. CONCLUSIONS: Our study did not show any statistically significant difference in the detection of malignant effusion in the 25 mL, 50 mL, and 150 mL group.

Nonepithelial Neoplasms of the Pancreas: Radiologic-Pathologic Correlation, Part 1--Benign Tumors: From the Radiologic Pathology Archives.

Solid and cystic pancreatic neoplasms are being recognized more frequently with increasing utilization and spatial resolution of modern imaging techniques. In addition to the more common primary pancreatic solid (ductal adenocarcinoma) and cystic neoplasms of epithelial origin, nonepithelial neoplasms of the pancreas may appear as well-defined solid or cystic neoplasms. Most of these lesions have characteristic imaging features, such as a well-defined border, which allows differentiation from ductal adenocarcinoma. Solid masses include neurofibroma, ganglioneuroma, leiomyoma, lipoma, and perivascular epithelioid cell tumor (PEComa). Schwannomas and desmoid tumors can be solid or cystic. Cystic tumors include mature cystic teratoma and lymphangioma. Lipoma, PEComa, and mature cystic teratoma can contain fat, and ganglioneuroma and mature cystic teratoma may contain calcification. Although these unusual benign neoplasms are rare, the radiologist should at least consider them in the differential diagnosis of well-defined lesions of the pancreas. The goal of this comprehensive review is to improve understanding of these rare primary pancreatic mesenchymal tumors.

Pancreatic endocrine tumors: radiologic-clinicopathologic correlation.

Pancreatic endocrine tumors (PETs) are primarily well-differentiated tumors composed of cells that resemble normal islet cells but that arise from pancreatic ductal cells. They are classified as functioning or nonfunctioning according to their associated clinical symptoms; insulinoma, gastrinoma, and glucagonoma are the most common functioning PETs. They also are classified according to their biologic behavior, although all PETs have malignant potential. Most are sporadic, but some are associated with familial syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, and neurofibromatosis type 1. At imaging, PETs typically appear as well-defined hypervascular masses, a finding indicative of their rich capillary network. Cystic change, calcification, and necrosis are common in large tumors, which are associated with a poorer prognosis and a higher prevalence of local and vascular invasion and metastases than are smaller tumors. Even when metastases are present, many well-differentiated PETs have an indolent course. Poorly differentiated PETs are rare and have an infiltrative appearance; patients with such tumors have a poor prognosis. Knowledge of the characteristic clinical, pathologic, and radiologic features of PETs is important in the evaluation and management of patients with a suspected clinical syndrome or a pancreatic mass.

Multiple bony amyloidomas as an initial presentation of myeloma.

Amyloidosis complicating multiple myeloma is an uncommon but well-recognized phenomenon. Multiple bone amyloidomas are rare as the initial presenting feature of myeloma. Solitary bone amyloidomas share common features with those of patients who have solitary plasmacytomas and progression to disseminated myeloma is common. We report a case of an elderly man who presented with extensive amyloid deposition in multiple plasmacytoma sites as well as evidence of amyloid in a fat pad aspirate but with none of the usual organ damage associated with systemic amyloidosis. This presentation is similar to a subset of patients said to have macrofocal myeloma. These patients are typically aged < 40 years, have no bone marrow involvement, and have a good prognosis. This report may represent the first description of macrofocal myeloma associated with amyloid deposition in an older individual.

Construction and validation of tissue microarrays of ductal carcinoma in situ and terminal duct lobular units associated with invasive breast carcinoma.

Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.0-mm diameter needles, we constructed TMAs from specimens obtained from 32 women with breast cancer containing the following targets: (1) 28 terminal duct lobular units (TDLUs); (2) 28 ductal carcinomas in situ, and (3) 23 invasive carcinomas. Using careful target selection, we achieved representation of approximately 80% of noninvasive targets with sustained preservation through section 30 of the TMAs. Immunohistochemical staining of TDLU targets demonstrated positive staining for estrogen receptor (ER) in 30.8% of tubules and for progesterone receptor (PR) in 50.0%. To establish an efficient method to evaluate staining results in TDLUs, we created a categorical scoring system to approximate the percentage of tubules containing positive stained cells (<10%, 10% to 50%, >or=50%), and compared the results with those obtained by tubule counting. Comparison between the two methods demonstrated exact agreement for 70.8% of ER and 79.2% of PR stains without two-category discrepancies. ER/PR expression levels in multiple (up to 4) noninvasive targets of the same tissue type (TDLU or DCIS) from a single block showed good correlation. These data suggest that it is feasible to produce TMAs of noninvasive breast structures, albeit with careful selection of targets, and that immunostains of such cores may permit efficient immunohistochemical characterization of peritumoral tissues. Additional exploration of this approach is needed.

Gastrointestinal glomus tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 32 cases.

Glomus tumors usually occur in the peripheral soft tissues, but similar tumors have also been reported in the stomach and occasionally in the intestines. However, the relationship of these tumors to peripheral glomus tumors and gastrointestinal stromal tumors has not been fully clarified because previous series of gastrointestinal glomus tumors predate availability of immunohistochemistry. This clinicopathologic study examined 32 gastrointestinal glomus tumors. All but one of the tumors were located in the stomach and the remaining tumor was from the cecum. The tumors occurred with a strong female predominance (23 females and 9 males) and a median age of 55 years (range 19-90 years). The gastric tumors typically presented with gastrointestinal bleeding or ulcer-like symptoms, and 14 tumors had mucosal ulceration. Five tumors were incidental findings. The tumor sizes varied from 1.1 to 7 cm (median 2 cm), and most were located in the antrum. Histologically, the tumors typically had a solid pattern of sharply demarcated, round glomus cells with prominent, mildly dilated pericytoma-like vessels. Vascular invasion and focal atypia were relatively common (seen in 11 and 13 cases, respectively), and low mitotic activity (1-4 per 50 high power fields), was seen in 10 cases. Immunohistochemically, all tumors were positive for alpha-smooth muscle actin and calponin, and nearly all had a net-like pericellular laminin and collagen type IV positivity. All tumors were negative for desmin and S-100 protein. Three tumors had focal synaptophysin positivity, but none was positive for chromogranin. All tumors lacked KIT expression and the GIST-specific mutations in the c-kit gene. Follow-up revealed one patient death of metastatic disease to liver at 50 months; this tumor had 1 mitosis per 50 high power fields, but had spindle cell foci, mild atypia, and vascular invasion. Thirteen patients were well and alive after long-term follow-up. Gastrointestinal glomus tumors occur almost exclusively in the stomach, and they have a good overall prognosis, but a small, unpredictable potential for malignant behavior exists. These tumors are phenotypically similar to peripheral glomus tumors and differ from epithelioid GISTs.