NHERF1/EBP50 immunoexpression in renal cell carcinomas and oncocytomas with ultrastructural analysis of clear cell renal cell carcinoma.

Background: Na+/H+ exchanger (NHE) maintains the alkaline pH of epithelial cells working at the cellular membrane and exchanging H+/Na+ ions. In renal tubular epithelial cells, the reabsorption of NaCl is implemented by NHE3 isoform, which is regulated by NHE regulatory factor-1 (NHERF1). Normally situated at the apical zones of proximal tubular cells, NHERF1 participates in cytoskeletal reorganization and signal transduction facilitating structural stability and ion exchange. Based on an extensive search in English literature, NHERF1/EBP50 immunoexpression has been studied in breast, colon, and other tumors with only one study on 21 cases of renal cell carcinomas (RCC). Methods: Using NHERF1/EBP50 immunohistochemistry (IHC) on 64 (82%) RCCs (34 clear cells, 21 papillary and 9 chromophobe types) and 14 (18%) oncocytomas, we evaluated and scored NHERF1/EBP50 immunoexpression depending on the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system followed by ultrastructural identification of microlumen-like structures (MLS) in clear cell renal cell carcinomas (ccRCC). Results: Staining patterns varied throughout the tumors and within individual tumors. Only ccRCC showed unique MLS within the cytoplasm of tumor cells. All neoplasia-transformed tubular cells, regardless of the tumor grade and stage, had altered immunoexpression of NHERF1/EBP50 ranging from complete absence to aberrant expression in the luminal cell membrane, nuclear or cytoplasmic localizations. Conclusions: Only ccRCC showed unique dot-like condensations of immunostaining/MLS at membranous, submembranous, and paranuclear localizations. The latter two localizations were mainly observed in the combined WHO/ISUP grade 1 and 2 group compared to the combined group of grade 3 and 4 tumor samples (P=0.0146 and P<0.0001, respectively). Ultrastructurally, the MLS were identified as thick microvilli trapped by a single-layer membrane, displaced into the cytoplasm and ranging from 400 nm to 3.5 µm. These significant ultrastructural reorganizations may contribute to tumor progression, metastasis, and drug resistance.

Severe rash after COVID-19 vaccination.

The patient's recent vaccine was the most remarkable thing about his medical history.

Histopathological evidence that diethylene glycol produces kidney and nervous system damage in rats.

Diethylene glycol (DEG) is an organic compound that has been found as an adulterant in consumer products as a counterfeit glycerin. Diethylene glycol is metabolized to two primary metabolites: 2-hydroxyethoxyacetic acid (2-HEAA) and diglycolic acid (DGA), the latter shown to accumulate in the kidney and cause dose-dependent cell necrosis. DEG poisonings are characterized predominately by acute kidney injury (AKI) but have also produced delayed neurological sequelae such as sensorimotor neuropathy. To better understand these effects, Wistar-Han rats were orally administered a water control or doses of 4 g/kg-6 g/kg DEG every 12 or 24 h for 7 days, with kidney, brain, and spinal cord tissue collected for histopathological analysis. This dosing paradigm resulted in approximately 25 % of the DEG-treated animals developing AKI and also neurotoxicity (sensorimotor dysfunction and elevated cerebrospinal fluid (CSF) protein). Kidney pathology included a severe, diffuse acute kidney tubular necrosis predominantly affecting proximal convoluted tubules. Scattered birefringent crystals consistent with calcium oxalate monohydrate were also found in the proximal tubule of animals with AKI. Demyelination in the dorsal and lateral white matter regions of the cervical, thoracic, and lumbar areas of the spinal cord of a DEG-treated animal with AKI was documented, establishing the neuropathology in DEG-treated animals that developed neurotoxicity. There were significant changes in amino acid concentrations in the CSF that may reflect the neurotoxicity of DEG, specifically glutamate and glutamine, but with no ammonia change. These studies characterized the pathologic aspects of the neurotoxicity in a DEG repeat-dose model.

Metastatic renal cell carcinoma presenting as subcutaneous nodule.

Renal cell carcinoma is frequently undiagnosed until it reaches an advanced metastatic stage. Renal cell cancers are also seen as incidental findings on imaging, and rarely can present as physical examination findings. We report a rare case where metastatic renal cell carcinoma presented as a solitary 2 cm subcutaneous chest wall nodule in an otherwise asymptomatic male patient. Initial ultrasound evaluation showed a solid vascular subcutaneous mass, a fine needle aspiration suggested metastatic renal cell cancer, and later, excision biopsy, and CT scan of the abdomen made the final diagnosis of stage IV renal cell carcinoma. The differential diagnosis of a 2 cm nodule can be broad and in appropriate clinical setting should include consideration of malignancy and/ metastasis.

Bilateral ptosis/blepharitis due to lepromatous leprosy.

PURPOSE: To underscore the importance of histopathological evaluation in cases presenting with a constellation of unusual ocular inflammation and physical findings. OBSERVATION: A 51-year-old male, presented with a chief complaint of worsening visual field loss due to droopy eyelids two months post excision of a right upper eyelid squamous cell carcinoma. His past medical history included chronic edematous facial features, chronic sinusitis, unexplained peripheral neuropathy, and worsening fatigue. Pre-blepharoplasty work-up revealed mechanical ptosis from lid edema, madarosis, a concave nasal bridge, pancytopenia, and numerous burn marks due to inadvertent injuries. Bilateral blepharoplasty was performed, and the excised tissue submitted for histopathological evaluation that revealed non-caseating granulomatous perineural inflammation with numerous acid-fast bacilli in dermal layers and nerves. These findings prompted a diagnosis of lepromatous leprosy with suspected bone marrow involvement. The source of the infection was unknown. The blepharoplasty restored his visual fields and multi-drug therapy (MDT) improved his general health and wellbeing with concomitant reductions of pancytopenia, fatigue, and facial edema. CONCLUSIONS AND IMPORTANCE: Biopsy histopathology, in patients with longstanding ocular adnexal inflammation, can facilitate diagnosis and treatment. To the authors' knowledge, this is an unusual ocular leprosy presentation and represents the first leprosy case diagnosed via blepharoplasty.

Prostate cancer metastatic to bilateral testicles: case report and literature review.

PURPOSE: Hormone-refractory prostate cancer (PCa) has a high incidence of metastasis with common secondary site locations. Our case report describes a rare metastatic site of PCa infiltrating bilateral testicles in the absence of definitive radiologic evidence. MATERIALS AND METHODS: Following the patient's consent and IRB exemption, we report the clinical, radiological, and pathological presentation of the patient treated at our institution. We also conducted an inclusive literature review of PCa with bilateral testicular metastases. RESULTS: Our patient is a 54-year-old male who presented to the emergency room with lower urinary tract symptoms and failure to void. A full workup including digital rectal examination, PSA (580 ng/ml), and a transrectal ultrasound (TRUS) biopsy performed afterward revealed an adenocarcinoma of the prostate. The metastatic workup at presentation was negative. After failure to comply with treatment guidelines, the patient was referred back to us with bilateral testicular masses. Without clear evidence of the origin of the masses, bilateral orchiectomy was performed, and pathological analysis confirmed it was metastatic prostate adenocarcinoma. Post-orchiectomy, the patient was again lost to follow up. Three years later the patient returns and placed in palliative care. CONCLUSIONS: This case report highlights that PCa can have a highly variable course and progression can occur in the absence of adherence to treatment. Any evidence of disease relapse and clinical suspicion of metastasis should be investigated, especially in patients with advanced and metastatic disease or poor adherence to surveillance protocol.

Intratracheal parathyroid gland: an unexpected diagnosis.

Ectopic or supernumerary parathyroid tissue has been generally described in the literature in cases found during workup for parathyroid adenoma. We present two unique cases of intratracheal parathyroid gland, a rare occurrence that has not yet been described in the literature. In both cases, the masses were found incidentally and showed no clinical or laboratory evidence of hyperparathyroidism. In both cases, surveillance was chosen as the method of treatment. We present this case series to increase awareness of this potential diagnosis.

Sternoclavicular Amyloid Arthropathy in a Patient With End-Stage Renal Disease.

Amyloidosis is an extracellular deposition of amyloid located in different organs or in a systemic distribution. We present a case of a 78 year-old male with hemodyalisis assosciated amyloidosisis involving the right sternoclavicular joint. Clinical and imaging implications are described.

Primary facial nerve paraganglioma: report and review of the literature.

This report describes the diagnosis and treatment of a patient with a rare primary facial nerve paraganglioma as well as a review of the current literature. A 60-year-old male patient presented to our clinic with a 4-month history of left-sided progressive facial paralysis House-Brackmann V. Biopsy taken during facial nerve (FN) decompression confirmed the diagnosis of paraganglioma. The left FN was sacrificed during resection of the mass and a 12-7 jump graft, using the left greater auricular nerve, was performed with acceptable outcomes. The rarity of these tumours does not discount their clinical importance or the necessity to include them in the differential when presented with unilateral FN paralysis. Investigation should begin with CT and MRI imaging to identify and localise the potential mass. Histologic confirmation requires tissue. While surveillance imaging is occasionally an option, often complete surgical resection of the mass and sacrifice of the nerve is necessary.

A case of HIV associated cryptococcal nephritis: Ultrastructural findings and literature review.

Acute renal failure in the setting of infection with human immunodeficiency virus can be due to various causes including pre-renal causes such as hypotension, sepsis, and nephrotoxic agents; thrombotic microangiopathy; or direct renal parenchymal infections by opportunistic organisms. We present a case of cryptococcal nephritis in a patient with systemic cryptococcosis and discuss the clinical findings as well as the histological, immunofluorescent, and transmission electron microscopy findings in the renal biopsy.

Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: involvement of the RB-microRNA axis.

BACKGROUND: The HECT family ubiquitin ligase Smurf2 regulates cell polarity, migration, division, differentiation and death, by targeting diverse substrates that are critical for receptor signaling, cytoskeleton, chromatin remodeling and transcription. Recent studies suggest that Smurf2 functions as a tumor suppressor in mice. However, no inactivating mutation of SMURF2 has been reported in human, and information about Smurf2 expression in human cancer remains limited or complicated. Here we demonstrate that Smurf2 expression is downregulated in human breast cancer tissues, especially of the triple-negative subtype, and address the mechanism of Smurf2 downregulation in triple-negative breast cancer cells. METHODS: Human breast cancer tissues (47 samples expressing estrogen receptor (ER) and 43 samples with triple-negative status) were examined by immunohistochemistry for the expression of Smurf2. Ten widely-studied human breast cancer cell lines were examined for the expression of Smurf2. Furthermore, microRNA-mediated regulation of Smurf2 was investigated in triple-negative cancer cell lines. RESULTS: Immunohistochemical analysis showed that benign mammary epithelial cells expressed high levels of Smurf2, so did cells in ductal carcinomas in situ. In contrast, invasive ductal carcinomas showed focal or diffuse decrease in Smurf2 expression, which was observed more frequently in triple-negative tumors than in ER-positive tumors. Consistently, human triple-negative breast cancer cell lines such as BT549, MDA-MB-436, DU-4475 and MDA-MB-468 cells showed significantly lower expression of Smurf2 protein, compared to ER + or HER2+ cell lines. Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple-negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. Forced expression of RB increased levels of Smurf2 protein with concomitant decreases in the expression of the microRNAs. CONCLUSIONS: This study provides evidence of posttranscriptional downregulation of Smurf2 in triple-negative breast cancers, and demonstrates that the loss of RB function is involved in microRNA-mediated interference with Smurf2 translation. The new link from RB inactivation to Smurf2 downregulation is likely to play a role in malignant phenotypes of triple-negative breast cancer cells.

Low-level amplification of oncogenes correlates inversely with age for patients with nontypical meningiomas.

BACKGROUND: This study sought to identify genes in nontypical meningiomas with gains in copy number (CN) that correlate with earlier age of onset, an indicator of aggressiveness. METHODS: Among 94 adult patients, 91 had 105 meningiomas that were histologically confirmed. World Health Organization grades I (typical), II (atypical), and III (anaplastic) were assigned to tumors in 76, 14, and 1 patient, respectively. Brain invasion indicated that two World Health Organization grade I meningiomas were biologically atypical. DNA from 15 invasive/atypical/anaplastic meningiomas and commercial normal DNA were analyzed with multiplex ligation dependent probe amplification. The CN ratios (fold differences from normal) for 78 genes were determined. The CN ratio was defined as [tumor CN]/[normal CN] for each gene to normalize results. RESULTS: Characteristic gene losses (CN ratio < 0.75) occurred in >50% of the invasive/atypical/anaplastic meningiomas at 22q11, 1p34.2, and 1p22.1 loci. Gains (CN ratio ≥ 2.0) occurred in each tumor for 2 or more of 19 genes. Each of the 19 genes' CN ratio was ≥ 2.0 in multiple tumors, and their collective sums (up to 49.1) correlated inversely with age (r = -0.72), minus an outlier. In patients ≤ 55 versus >55 years, 5 genes (BIRC2, BRAF, MET, NRAS, and PIK3CA) individually exhibited significantly higher CN ratios (P < 0.05) or a trend for them (P < 0.09), with corrections for multiple comparisons, and their sums correlated inversely with age (r = -0.74). CONCLUSIONS: Low levels of amplification for selected oncogenes in invasive/atypical/anaplastic meningiomas were higher in younger adults, with the CN gains potentially underlying biological aggressiveness associated with early tumor development.