Clinical Significance of SOX10 Expression in Human Pathology.

The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, SOX10, a member of the SOX gene family, stands out. Located on chromosome 22q13, the SOX10 gene encodes a transcription factor crucial for the differentiation, migration, and maintenance of tissues derived from neural crest cells. It plays a pivotal role in developing various tissues, including the central and peripheral nervous systems, melanocytes, chondrocytes, and odontoblasts. Mutations in SOX10 have been associated with congenital disorders such as Waardenburg-Shah Syndrome, PCWH syndrome, and Kallman syndrome, underscoring its clinical significance. Furthermore, SOX10 is implicated in neural and neuroectodermal tumors, such as melanoma, malignant peripheral nerve sheath tumors (MPNSTs), and schwannomas, influencing processes like proliferation, migration, and differentiation. In mesenchymal tumors, SOX10 expression serves as a valuable marker for distinguishing between different tumor types. Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies.

The Usefulness of Elastin Staining to Detect Vascular Invasion in Cancer.

Tumor prognosis hinges on accurate cancer staging, a pivotal process influenced by the identification of lymphovascular invasion (LVI), i.e., blood vessel and lymphatic vessel invasion. Protocols by the College of American Pathologists (CAP) and the World Health Organization (WHO) have been established to assess LVI in various tumor types, including, but not limited to, breast cancer, colorectal cancer (CRC), pancreatic exocrine tumors, and thyroid carcinomas. The CAP refers to blood vessel invasion as "angioinvasion" (vascular invasion) to differentiate it from lymphatic vessel invasion (lymphatic invasion). For clarity, the latter terms will be used throughout this review. The presence of lymphatic and/or vascular invasion has emerged as a pivotal prognostic factor; therefore, its accurate identification is crucial not only for staging but also for providing the patient with an honest understanding of his/her prognosis. Given the prognostic importance of the correct identification of LVI, specific staining techniques are employed to distinguish lymphatic vessel invasion from angioinvasion and to differentiate true LVI from artifact. These encompass hematoxylin and eosin (H&E) staining, elastic staining, Factor VIII staining, Ulex europaeus I agglutinin staining, CD31, CD34, D2-40, ERG, and D2-40 (podoplanin) immunohistochemical (IHC) stains among others. Based on a review of numerous publications regarding the efficacy of various methods for LVI detection, elastin staining demonstrated superior accuracy and prognostic value, allowing for more targeted treatment strategies. The clinical significance of accurately detecting LVI cannot be overstated, as it is strongly linked to higher cancer-related mortality and an increased risk of tumor recurrence. This review aims to examine the existing literature on the use of elastin stains in the detection of vascular invasion among different types of tumors and its prognostic value.

Unraveling the Mysteries of Perineural Invasion in Benign and Malignant Conditions.

Perineural invasion (PNI) is defined as the dissemination of neoplastic cells within the perineural space. PNI can be a strong indicator of malignancy and is linked to poor prognosis and adverse outcomes in various malignant neoplasms; nevertheless, it can also be seen in benign pathologic conditions. In this review article, we discuss various signaling pathways and neurotrophic factors implicated in the development and progression of PNI. We also describe the methodology, benefits, and limitations of different in vitro, ex vivo, and in vivo models of PNI. The spectrum of presentation for PNI can range from diffuse spread within large nerves ("named" nerves) all the way through localized spread into unnamed microscopic nerves. Therefore, the clinical significance of PNI is related to its extent rather than its mere presence or absence. In this article, we discuss the guidelines for the identification and quantification of PNI in different malignant neoplasms based on the College of American Pathologists (CAP) and World Health Organization (WHO) recommendations. We also describe benign pathologic conditions and neoplasms demonstrating PNI and potential mimics of PNI. Finally, we explore avenues for the future development of targeted therapy options via modulation of signaling pathways involved in PNI.

Fluid Overload-Associated Large B-Cell Lymphoma: A Case Report and Review of Literature.

Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a new entity described in the fifth edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors (WHO-HAEM5). It refers to malignant lymphoma present with symptoms of serous effusions in body cavities (pleural, peritoneal, and/or pericardial) in the absence of an identifiable tumor mass. We present a case of an 82-year-old man with a history of atrial fibrillation and atrial flutter, status post-ablation, essential hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) type 2 who was referred to our hospital for shortness of breath due to recurrent pleural effusion. Right video-assisted thoracoscopy with right pleural biopsy was performed. Histopathological examination of the pleural biopsy revealed dense fibrous tissue, chronic inflammation, lymphoid aggregates, and granulation tissue, with no evidence of lymphoma. Cytology of the right pleural fluid revealed large lymphoid cells, which were positive for CD45, CD20, PAX-5, MUM-1, BCL2, BCL6, and MYC protein. They were negative for CD3, CD10, CD138, and HHV-8 by immunohistochemistry (IHC). Epstein-Barr virus (EBV) was negative by in situ hybridization (ISH). Due to the absence of any evidence of lymphoma elsewhere, a diagnosis of fluid overload-associated large B-cell lymphoma (FO-LBCL) was made. We provide a synopsis of the main clinicopathological features of FO-LBCL and the two main differential diagnoses, primary effusion lymphoma (PEL) and diffuse large B-cell lymphoma (DLBCL).

Splenic Rupture Secondary to Amyloidosis: A Case Report and Review of the Literature.

Amyloidosis is a term describing the extracellular deposit of fibrils composed of subunits of several different normal serum proteins in various tissues. Amyloid light chain (AL) amyloidosis contains fibrils that are composed of fragments of monoclonal light chains. Many different disorders and conditions can lead to spontaneous splenic rupture, including AL amyloidosis. We present a case of a 64-year-old woman with spontaneous splenic rupture and hemorrhage. A final diagnosis of systemic amyloidosis secondary to plasma cell myeloma was made with infiltrative cardiomyopathy and possible diastolic congestive heart failure exacerbation. We also provide a narrative review of all documented cases of splenic rupture associated with amyloidosis from the year 2000 until January 2023, along with the main clinical findings and management strategies.

Routine elastin staining improves venous invasion detection in colorectal carcinoma.

BACKGROUND: Colorectal carcinoma is the second most common cause of cancer-related deaths in North America. Invasion of tumor cells into lymphatic and blood vessels is an imperative step in the metastatic progression of colorectal carcinoma. OBJECTIVES: This is a before-and-after study conducted by the Department of Pathology and Laboratory Medicine of Mount Sinai Medical Center of Florida to assess the impact on venous invasion (VI) detection by implementing routine elastin staining on all tumor-containing blocks per case, where feasible, in colorectal carcinoma (CRC) resection specimens. METHODS: Clinicopathological parameters of CRC specimens were collected from January until December 2021 (n = 93) for the pre-implementation cohort and from January until December 2022 (n = 61) for the post-implementation cohort. RESULTS: VI detection was significantly increased in the post-implementation cohort at a rate of 50.8 % compared to only 18.6 % in the pre-implementation cohort. The majority of VI identified in the pre-implementation cohort was extramural (61.5 %), whereas in the post-implementation cohort it was intramural (41.9 %). On univariate analysis, implementation of routine elastin stain was associated with strikingly increased VI detection rates (OR = 4.5, p-value < 0.001). On multivariate analysis, after adjusting for other clinicopathologic variables, elastin staining retained its independent statistically significant impact on VI detection (OR = 2.6, p-value = 0.034). Of note, there were no significant differences in the pre- and post-implementation cohorts in the frequency of nodal metastases, tumor extent, histologic grade, perineural invasion, T stage or M stage. CONCLUSION: Based on our results and what has been published recently, we confirm an increase in the VI detection rate after implementing routine elastin staining on all tumor-containing blocks in CRC resection specimens.

Colonic Ganglioneuroma: A Combined Single-Institution Experience and Review of the Literature of Forty-Three Patients.

Ganglioneuromas (GNs) are rare, benign tumors composed of ganglion cells, nerve fibers, and glial cells. Three types of colonic GN lesions exist: polypoid GNs, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. Less than 100 cases of GN are documented in the literature. A 10-year retrospective search of the pathology database at our institution identified eight cases of colonic GNs. All cases were incidental. Seven of the eight cases presented with colonoscopy findings of small sessile polyps (ranging between 0.1 and 0.7 cm) treated with polypectomy, whereas one case showed a 4 cm partially circumferential and partially obstructing mass in the ascending colon, treated with right hemicolectomy. Almost two-thirds of the cases (5/8) demonstrated associated diverticulosis. All cases were positive for S100 protein and Synaptophysin via immunohistochemistry (IHC). No syndromic association was identified in any of the cases. We also conducted a comprehensive review using PubMed to identify cases of colonic GN reported in the literature. In total, 173 studies were retrieved, among which 36 articles met our inclusion criteria (35 patients and 3 cases on animals). We conclude that while most GNs are incidental and solitary small sessile lesions, many can be diffuse and associated with syndromes. In these cases, the tumor can result in bowel obstruction simulating adenocarcinoma.

Improving documentation of blood product administration using a standardized electronic health record-based system: a single-institution experience.

OBJECTIVES: To improve documentation of blood product administration by assessing the completion status of blood transfusions. In this way, we can ensure compliance with the Association for the Advancement of Blood & Biotherapies standards and facilitate investigation of potential blood transfusion reactions. METHODS: This before-and-after study includes the implementation of an electronic health record (EHR)-based, standardized protocol for documenting the completion of blood product administration. Twenty-four months of retrospective data (January-December 2021) and prospective data (January-December 2022) were collected. Meetings were held before the intervention. Ongoing daily, weekly, and monthly reports were prepared, and targeted education to deficient areas as well as spot in-person audits by the blood bank residents were conducted. RESULTS: During 2022, 8,342 blood products were transfused, of which 6,358 blood product administrations were documented. The overall percentage of completed transfusion order documentation improved from 35.54% (units/units) in 2021 to 76.22% (units/units) in 2022. CONCLUSIONS: Interdisciplinary collaborative efforts helped produce quality audits to improve the documentation of blood product transfusion through a standardized and customized EHR-based blood product administration module.

Epithelial-to-Mesenchymal Transition-Related Markers in Prostate Cancer: From Bench to Bedside.

Prostate cancer (PCa) is the second most frequent type of cancer in men worldwide, with 288,300 new cases and 34,700 deaths estimated in the United States in 2023. Treatment options for early-stage disease include external beam radiation therapy, brachytherapy, radical prostatectomy, active surveillance, or a combination of these. In advanced cases, androgen-deprivation therapy (ADT) is considered the first-line therapy; however, PCa in most patients eventually progresses to castration-resistant prostate cancer (CRPC) despite ADT. Nonetheless, the transition from androgen-dependent to androgen-independent tumors is not yet fully understood. The physiological processes of epithelial-to-non-epithelial ("mesenchymal") transition (EMT) and mesenchymal-to-epithelial transition (MET) are essential for normal embryonic development; however, they have also been linked to higher tumor grade, metastatic progression, and treatment resistance. Due to this association, EMT and MET have been identified as important targets for novel cancer therapies, including CRPC. Here, we discuss the transcriptional factors and signaling pathways involved in EMT, in addition to the diagnostic and prognostic biomarkers that have been identified in these processes. We also tackle the various studies that have been conducted from bench to bedside and the current landscape of EMT-targeted therapies.

Potential diagnostic utility of PRAME and p16 immunohistochemistry in melanocytic nevi and malignant melanoma.

BACKGROUND: PRAME (PReferentially expressed Antigen in MElanoma) is a tumor-associated antigen that has been studied in various cutaneous melanocytic lesions. p16, on the other hand, has been proposed to aid in distinguishing between benign and malignant melanocytic neoplasms. Studies on the diagnostic utility of PRAME and p16 in combination in differentiating nevi from melanoma are limited. We aimed to assess the diagnostic utility of PRAME and p16 in melanocytic tumors and their role in distinguishing between malignant melanomas and melanocytic nevi. METHODS: This is a single-center retrospective cohort analysis over a 4-year period (2017-2020). We used the pathological database of malignant melanomas (77 cases) and melanocytic nevi (51 cases) specimens from patients who underwent shave/punch biopsies or surgical excisions and evaluated immunohistochemical staining percentage positivity and intensity for PRAME and p16. RESULTS: Most malignant melanomas showed positive/diffuse PRAME expression (89.6%); on the other hand, 96.1% of nevi did not express PRAME diffusely. p16 was expressed consistently in nevi (98.0%). However, p16 expression in malignant melanoma was infrequent in our study. PRAME had a sensitivity and specificity of 89.6% and 96.1%, respectively, for melanomas versus nevi; on the other hand, p16 had a sensitivity and specificity of 98.0% and 28.6%, respectively, for nevi versus melanoma. Also, a PRAME+/p16- melanocytic lesion is unlikely to be a nevus where most nevi were PRAME-/p16+. CONCLUSION: In conclusion, we confirm the potential utility of PRAME and p16 for distinguishing melanocytic nevi from malignant melanomas.

Anti-Cancer Stem-Cell-Targeted Therapies in Prostate Cancer.

Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men around the world. It is treated using a risk stratification approach in accordance with the National Comprehensive Cancer Network (NCCN) in the United States. The main treatment options for early PCa include external beam radiation therapy (EBRT), brachytherapy, radical prostatectomy, active surveillance, or a combination approach. In those with advanced disease, androgen deprivation therapy (ADT) is considered as a first-line therapy. However, the majority of cases eventually progress while receiving ADT, leading to castration-resistant prostate cancer (CRPC). The near inevitable progression to CRPC has spurred the recent development of many novel medical treatments using targeted therapies. In this review, we outline the current landscape of stem-cell-targeted therapies for PCa, summarize their mechanisms of action, and discuss avenues of future development.

Brenner Tumor of the Ovary: A 10-Year Single Institution Experience and Comprehensive Review of the Literature.

Brenner tumors (BTs) are surface-epithelial stromal cell tumors that are categorized by the World Health Organization as benign, borderline, and malignant. Due to the rarity of BTs, the published literature on these tumors is comprised primarily of case reports and small retrospective studies. We performed a pathology database review spanning the last ten years at our institution revealing nine reported benign BTs. We collected the clinical and pathological data of patients associated with those BTs, describing the clinical presentation and imaging results, and assessing the possible risk factors associated with them. The average age at diagnosis was 58 years. BTs were discovered incidentally in 7/9 cases. The tumor was multifocal and bilateral in 1/9 cases and ranged in size from 0.2 cm to 7.5 cm. Associated Walthard rests were found in 6/9 cases and transitional metaplasia of surface ovarian and/or tubal epithelium was found in 4/9 cases. One patient had an associated mucinous cystadenoma in the ipsilateral ovary. Another patient had an associated mucinous cystadenoma in the contralateral ovary. In conclusion, we found that Walthard rests and transitional metaplasia are common findings in association with BTs. Additionally, pathologists and surgeons need to be aware of the association between mucinous cystadenomas and BTs.

PIK3R1, HRAS and AR Gene Alterations Associated with Sclerosing Polycystic Adenoma of the Parotid Gland.

Sclerosing polycystic adenoma (SPA) is a rare neoplasm occurring in the salivary glands, mainly the parotid gland. Although it was originally thought to represent a non-neoplastic process, recent genetic data have proven its monoclonality, supporting its neoplastic origin. We report a case of a 73-year-old woman who presented with left neck swelling and pain. A 3 cm hypoechoic, heterogeneous, solid mass was identified on neck ultrasonography within the left parotid gland. Fine needle aspiration revealed benign acinar cells and lymphocytes. Left partial superficial parotidectomy was performed and a diagnosis of SPA was made. Targeted next-generation sequencing (NGS) revealed three clinically significant alterations in the PIK3R1, HRAS, and AR genes. Alterations in the PIK3R1 gene have been previously reported in cases of SPA; however, this study is the first to report two novel clinically significant genomic alterations in the HRAS and AR genes. AR protein expression by immunohistochemistry was strongly and diffusely positive in the neoplastic epithelial cells compared to the adjacent normal salivary gland tissue, which was dead negative for AR. This molecular profile will enhance our understanding of the molecular pathways underlying the development of this tumor. Although this entity was initially thought to be a reactive process, evidence from our case and similar cases strongly support the notion that it is neoplastic due to the presence of specific genetic alterations linked to it.

Recurrent PIK3CA H1047R-Mutated Congenital Infiltrative Facial Lipomatosis: A Case Report and Review of Literature.

Congenital infiltrating lipomatosis of the face (CILF) is a rare, congenital, nonhereditary facial overgrowth due to post-zygomatic activating mutations in PIK3CA gene. It is unilateral and involves hypertrophy of both the soft and hard tissue structures on the affected side of the face. This commonly results in early eruption of the teeth, hypertrophy of the facial bones, macroglossia, and proliferation of the parotid gland. Less than 80 cases of CILF have been reported in the literature so far. Treatment modalities include liposuction and surgical excision. However, since the hallmark of CILF is mutation in the PIK3CA gene, PI3K inhibitors may play a therapeutic role in CILF. We report a case of an 8-year-old boy with recurrent CILF of the scalp and nose, with PIK3CA H1047R mutation. We discuss the differential diagnoses, clinical outcomes, and management of this rare entity.

Prognostic Significance of p53 and p63 in Diffuse Large B-Cell Lymphoma: A Single-Institution Experience.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. We evaluated the immunohistochemical (IHC) expression of p63 and p53 in DLBCL and their significance on overall survival (OS) and progression-free survival (PFS). We conducted a retrospective cohort study of 177 patients with DLBCL who presented to Mount Sinai Medical Center of Florida (Miami Beach, Florida) between 2010 and 2020. IHC staining for p63 and p53 protein expression was performed. A significant correlation was found between p63 positivity and p53 expression, p53/p63 co-positivity, Ki-67 proliferation index, MYC expression, and MYC/BCL2 double expression. Regardless of the germinal center B-cell like (GCB) subgrouping, there was a trend among p53+ patients to have MYC/BCL2 double expression, positive MYC expression, and lower OS and PFS. A tendency of poor OS was seen in p53+ patients in the non-GCB, GCB, and double expressors subgroups and poor PFS in p53+ patients regardless of the subgrouping. In conclusion, our results suggest that p63 and p53 may represent potential additional prognostic biomarkers in DLBCL and may be included in the initial diagnostic work up of patients with DLBCL.

Drug Repurposing in Non-Small Cell Lung Carcinoma: Old Solutions for New Problems.

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in 2022. The majority (80%) of lung cancer cases belong to the non-small cell lung carcinoma (NSCLC) subtype. Despite the increased screening efforts, the median five-year survival of metastatic NSCLC remains low at approximately 3%. Common treatment approaches for NSCLC include surgery, multimodal chemotherapy, and concurrent radio and chemotherapy. NSCLC exhibits high rates of resistance to treatment, driven by its heterogeneity and the plasticity of cancer stem cells (CSCs). Drug repurposing offers a faster and cheaper way to develop new antineoplastic purposes for existing drugs, to help overcome therapy resistance. The decrease in time and funds needed stems from the availability of the pharmacokinetic and pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved drugs to be repurposed. This review provides a synopsis of the drug-repurposing approaches and mechanisms of action of potential candidate drugs used in treating NSCLC, including but not limited to antihypertensives, anti-hyperlipidemics, anti-inflammatory drugs, anti-diabetics, and anti-microbials.

Diffuse pulmonary ossification: A case report unveiling clinical and histopathological challenges.

Diffuse pulmonary ossification (DPO) is a rare pulmonary condition characterized by the diffuse formation of mature bone in the lungs. Pulmonary ossification, in general, can be subdivided into diffuse pulmonary ossification (DPO) and nodular pulmonary ossification (NPO). DPO occurs most commonly in the settings of chronic pulmonary conditions; however, idiopathic cases have been reported. We present a case of DPO in a 36-year-old man with progressive exertional dyspnea, productive cough, and occasional hemoptysis. Imaging studies showed innumerable pulmonary nodules scattered throughout both lungs. Initially, the diagnoses of pulmonary alveolar microlithiasis (PAM) or, less likely miliary tuberculosis (TB) were considered. However, Quantiferon TB test was negative and genetic testing was negative for SLC34A2, lowering the probability of PAM. The patient underwent a segmentectomy. Microscopic examination showed ramifying spicules of mature woven bone and fatty marrow consistent with DPO. There were no significant underlying pathologic findings, such as interstitial fibrosis, granulomas, organizing pneumonia, or significant inflammation in the background lung parenchyma. In conclusion, clinicians and radiologists need to be aware of DPO in the differential diagnosis of miliary tuberculosis and pulmonary alveolar microlithiasis. The absence of an underlying chronic pulmonary condition does not exclude the possibility of DPO.

RETRACTED: Bahmad et al. Histopathologic Findings Associated with Miller-Dieker Syndrome: An Autopsy Report. Diseases 2022, 10, 95.

The Journal retracts the article, Histopathologic Findings Associated with Miller-Dieker Syndrome: An Autopsy Report [...].

Novel ATM Gene c.5644 C > T (p.Arg1882*) Variant Detected in a Patient with Pancreatic Adenocarcinoma and Two Primary Non-Small Cell Lung Adenocarcinomas: A Case Report

Ataxia-telangiectasia is an autosomal recessive disorder that usually manifests in childhood due to mutations in the Ataxia-Telangiectasia Mutated (ATM) gene. It is believed that there is an association between this gene mutation/polymorphism and cancer risk, including breast, lung, and pancreatic cancers. We report a rare case of a 69-year-old woman who developed three different primary cancers, including non-small cell lung cancer (NSCLC) in both lungs and pancreatic adenocarcinoma, and was later found to have a rarely reported variant mutation in the ATM gene, namely Exon 39, c.5644 C > T. We hypothesize that the ATM gene, c.5644 C > T mutation could be a plausible contributor in the pathogenesis of these three cancers. This hypothesis has yet to be validated by larger studies that focus on a mechanistic approach involving DNA repair genes such as the ATM. More importantly, this paves the way to developing new patient-specific targeted therapies and inaugurating precision medicine as a cornerstone in cancer therapeutics.

Renal Cell Carcinoma Presenting as Syncope due to Saddle Pulmonary Tumor Embolism.

Pulmonary embolism (PE) is defined as the obstruction of the pulmonary artery or one of its branches by a blood clot, tumor, air, or fat emboli originating elsewhere in the body. A saddle PE occurs when the obstruction affects the bifurcation of the main pulmonary artery trunk. We present a case of a 46-year-old man who presented to our hospital due to an episode of syncope. Computed tomography angiography (CTA) of the chest showed extensive PE and abdominal CT scan showed a large 8 cm left renal mass with inferior vena cava (IVC) thrombus. Emergent embolectomy, left total nephrectomy, and IVC tumor removal were performed yielding the diagnosis of clear cell renal cell carcinoma (RCC). Interestingly, our patient did not experience any symptoms related to his RCC until the diagnosis of PE due to syncope, and the asymptomatic tumor was found out to be the possible cause of this PE due to the presence of tumor cells constituting the tumor embolus. It is thus recommended to improve the early screening process for RCC. Besides, clinicians should pay attention to patients presenting with uncharacteristic symptoms of RCC who might present with symptoms of saddle PE.