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.

Melanoma and Glioblastoma-Not a Serendipitous Association.

Recently, we came across a patient with malignant melanoma and primary glioblastoma. Given this, we parsed the literature to ascertain the relationship, if any, between these 2 malignancies. We begin with a brief overview of melanoma and glioma in isolation followed by a chronologic overview of case reports and epidemiologic studies documenting both neoplasms. This is followed by studies detailing genetic abnormalities common to both malignancies with a view to identifying unifying genetic targets for therapeutic strategies as well as to explore the possibility of a putative association and an inherited cancer susceptibility trait. From a scientific perspective, we believe we have provided evidence favoring an association between melanoma and glioma. Future studies that include documentation of additional cases, as well as a detailed molecular analyses, will lend credence to our hypothesis that the co-occurrence of these 2 conditions is likely not serendipitous.

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.

Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non-Langerhans cell histiocytosis: Case report and literature review.

Cutaneous non-Langerhans cell histiocytosis (NLCH) is a rare and biologically benign entity that can be broadly classified into two categories: xanthogranuloma and non-xanthogranuloma. The xanthogranuloma family is characterized by a proliferation of histiocytes with both macrophage and dendritic cell differentiation, negative BRAF mutation, and rare Touton-type giant cells. Molecular studies have reported that mutations involved in the MAPK signaling pathways are implicated in the pathophysiology of histiocytoses. While LCH is associated with the somatic mutation of BRAF v600e, however, mutations and gene fusions in NLCH cases are undefined. We hereby present a 19-month-old female with recalcitrant nodular rashes diagnosed as NLCH with associated novel genetic mutation involving ANKRD26 and PDGFRB genes, as well as PDGFRB::CD74 fusion mRNA. Immunohistochemical staining showed strong and diffuse CD68 and CD163 positivity, and negative CD1a, CD207, ALK D5F3, S100 protein, and BRAF V600E (VE1). Albeit unknown significance, this case of an ANKRD26 and PDGFRB gene mutation in cutaneous NLCH has not been reported prior in the literature. Our case highlights the advantage of pathology and genetic studies in cutaneous NLCH to increase the understanding of this heterogeneous enigmatic disorder and identify further options in management.

Role of VivaScope 2500 ex vivo confocal microscopy in skin pathology: Advantages, limitations, and future prospects.

BACKGROUND: Vivascope 2500 ex vivo confocal microscopy (EVCM) is an emerging optical imaging device that allows nuclear level resolution of freshly excised tissues. EVCM provides, rapid real-time pathological examination in many subspecialties of pathology including skin, prostate, breast, liver, etc. In contrast to traditional time-consuming frozen sectioning and histological analysis. AIMS: To evaluate the current state of EVCM utilization. MATERIALS AND METHODS: This study highlights the advantages, limitations, and prospects of EVCM in skin pathology. RESULTS: Our findings demonstrate that EVCM is a promising adjunctive tool to assess margins in Mohs surgery and to provide rapid, accurate diagnosis of cutaneous tumors, infectious and inflammatory diseases. CONCLUSION: EVCM is a revolutionary device that can be used as an adjunct to paraffin-fixed, hematoxylin and eosin-stained slides and frozen sectioning. Additional refinements are required before EVCM can be used as an alternative to frozen sectioning or traditional tissue processing.

Immunohistochemistry as a Genetic Surrogate in Dermatopathology: Pearls and Pitfalls.

Immunohistochemistry (IHC) is routinely performed in most laboratories, and other than purchase of commercially available antibodies, requires no additional equipment or reagents. As such, IHC is an accessible and relatively inexpensive test and one that can be performed quite quickly. This is in sharp contrast to genomic or mutational testing methodologies that are routinely "send out" tests as they require specialized equipment and reagents as well as individuals with expertise in the performance of the tests and analysis of the results, resulting in a prolonged turn-round-time and enhanced associated costs. However, many open questions remain in a rapidly changing therapeutic and scientific landscape with most obvious one being what exactly is the utility of "good old fashioned" IHC in the age of targeted therapy? For molecular applications, is a negative immunohistochemical result enough as a stand-alone diagnostic or predictive product? Is a positive immunohistochemical result perhaps more suitable for a role in screening for molecular alterations rather than a definitive testing modality? This review is an attempt to answer those very questions. We elucidate the broad range of entities in which IHC is currently used as a molecular surrogate and underscore pearls and pitfalls associated with each. Special attention is given to entities for which targeted therapies are currently available and to entities in which molecular data is of clinical utility as a prognosticator.

PD-L1 Detection-Pearls and Pitfalls Associated With Current Methodologies Focusing on Entities Relevant to Dermatopathology.

PD-L1 is a transmembrane glycoprotein with an extracellular as well as an intracellular cytoplasmic domain. Physiologically, it plays a pivotal role in regulating T-cell activation and tolerance. Many tumor cells have exploited this regulatory mechanism by overexpressing PD-L1 in an effort to escape immunologic surveillance. In this review, we parse the literature regarding the prognostic value of tumoral PD-L1 expression before discussing the various methodologies as well as the pearls and pitfalls associated with each for predicting response to anti-PD-1/PD-L1 therapies. Special attention is given to cutaneous entities in which PD-L1 expression has been documented with an emphasis on cutaneous malignancies that have seen the broadest applications of anti-PD-L1/PD-1 therapies. Currently, immunohistochemistry is the method that is most commonly used for detection of PD-L1. However, with the wide array of immunohistochemistry protocols and staining platforms available in the market, there seems to be different cutoffs not just for different entities but also for the same entity. This review is an attempt to address the need for standardization and validation of existing protocols for PD-L1 detection.

A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma.

Objectives: The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and BRCA2 in malignant mesothelioma and their putative impact on protein properties. Methods: Eighteen cases of malignant mesothelioma were retrieved from the archives and for next generation sequencing analysis of BRCA1 and BRCA2 genes. Variants were analyzed using Ensembl VEP17, Polyphen 2.0 software, SIFT software, MutpredV2, and SWISS-MODEL homology-modeling pipeline server. Results: BRCA2 variants were found in significantly higher percentage (22%) of cases (p=0.02). Five missense variants were identified. These were p.A2351P, p.T2250A, p.A895V, pG1771D, and p.R2034C. The SIFT scores of all except one were ≥ 0.03. The Polyphen scores of these four alterations were ≤0.899. In case of p.A2315, the SIFT score was 0.01, while the Polyphen 2 score was 0.921. MutPred2 scores were ≤0.180 for all. Loss of intrinsic disorder was predicted (Pr=0.32, p=0.07) for p.R2034C, while gain of intrinsic disorder was predicted for p.A2351P (Pr=0.36, p=0.01) and p.G1771D (Pr=0.34, p=0.02). Conclusions: BRCA2 somatic variants were identified in 22% cases of malignant mesotheliomas in this study. The variants localize more frequently to the disordered regions of the protein and are predicted to affect the level of disorder.

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.

Artificial intelligence and digital pathology: clinical promise and deployment considerations.

Artificial intelligence (AI) presents an opportunity in anatomic pathology to provide quantitative objective support to a traditionally subjective discipline, thereby enhancing clinical workflows and enriching diagnostic capabilities. AI requires access to digitized pathology materials, which, at present, are most commonly generated from the glass slide using whole-slide imaging. Models are developed collaboratively or sourced externally, and best practices suggest validation with internal datasets most closely resembling the data expected in practice. Although an array of AI models that provide operational support for pathology practices or improve diagnostic quality and capabilities has been described, most of them can be categorized into one or more discrete types. However, their function in the pathology workflow can vary, as a single algorithm may be appropriate for screening and triage, diagnostic assistance, virtual second opinion, or other uses depending on how it is implemented and validated. Despite the clinical promise of AI, the barriers to adoption have been numerous, to which inclusion of new stakeholders and expansion of reimbursement opportunities may be among the most impactful solutions.

Parathyroid hemangioma.

BACKGROUND: Hemangiomas are benign neoplasms of capillary proliferation that arise from a developmental anomaly where angioblastic mesenchyme fails to form canals. Most hemangiomas arise in the head and neck region, either superficially in the skin or deeper within endocrine organs such as the parotid gland. Parathyroid hemangiomas, however, are extremely rare, with only five cases previously reported in the literature. CASE PRESENTATION: Herein, we present a case of a 68-year-old man with a hemangioma almost completely replacing the right upper parathyroid gland, grossly measuring 1.3 × 1.3 × 1.2 cm and weighing 700 mg, associated with primary hyperparathyroidism. CONCLUSIONS: Parathyroid gland enlargement due to vascular neoplasms such as hemangiomas can mimic, both clinically and radiographically, hyperplasias and/or adenomas. Surgeons need to be aware of the presence of this entity and should consider it in the differential diagnosis of hyperparathyroidism or parathyroid gland enlargement.

Neonatal acute liver failure with pulmonary yellow hyaline membrane and kernicterus.

BACKGROUND: Neonatal acute liver failure (NALF) is a rare and life-threatening condition. It causes bilirubin to accumulate to a dangerous level in the body, causing permanent damage to vital organs such as the brain and lungs. In many cases, the etiology of NALF remains unknown. CASE PRESENTATION: We described a case of an 8-day-old baby girl who presented with poor oral intake, lethargy, and jaundice. Her clinical condition rapidly deteriorated with progression to multi-organ failure, and despite intensive resuscitation efforts, she expired. At autopsy, the most significant findings were liver necrosis, yellow hyaline membrane deposition in the lungs, and bilirubin deposition in the brain (kernicterus). CONCLUSIONS: NALF is a rare and potentially fatal condition necessitating prompt recognition and disease-specific treatment approaches. Toxic accumulation of bilirubin in the lungs can lead to hypoxia and precipitate further ischemic injury to the liver.

Pyoderma gangrenosum associated with limited cutaneous systemic sclerosis: a rare case with literature review.

Pyoderma gangrenosum (PG) is a skin disease characterized by painful ulcers that, when not appropriately treated, can lead to permanent disfigurement. Pyoderma gangrenosum has been observed in a multitude of autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease (IBD), and sarcoidosis (Feld et al. J Rheumatol. 39(1):197, 2012; Herrero et al. J Rheumatol. 36:7:1557-1558, 2009). It is rarely associated with autoimmune disorders such as systemic sclerosis. We report a case of a patient with known limited cutaneous systemic sclerosis who developed an ulcerated lesion on the 2nd digit of the left hand. The lesion was initially thought to be cellulitis and the patient underwent superficial wound debridement. Postoperatively, the patient's lesions worsened. The patient was treated with intravenous (IV) methylprednisolone and 0.05% topical clobetasol due to high suspicion for PG with complete resolution of ulcerated lesions and minimal scarring.

Cellular senescence evaluated by P16INK4a immunohistochemistry is a prevalent phenomenon in advanced calcific aortic valve disease.

BACKGROUND: Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific aortic valve disease (CAVD), a leading cause of morbidity and mortality in the aging population. Cellular senescence contributes to a functional decay in chronic diseases by intensifying tissue remodeling and impairing tissue regeneration. We evaluated the expression of P16INK4A and P53 as surrogate markers of senescence in CAVD. METHODS: Aortic valves from 27 individuals with severe CAVD requiring aortic valve replacement were selected for routine histologic processing. Immunohistochemical expression of P16INK4A and P53 was quantified using computerized image analysis on fields matching compartments with varying degrees of tissue remodeling. RESULTS: All aortic valves demonstrated P16INK4A and P53-positive cells. The percentage of P16INK4A -positive cells, but not of P53, was higher in areas of calcification and/or ossification (57.21%±26.31, n=40) and severe fibrosis (54.79%±27.19, n=25) than in areas with minimal to mild tissue remodeling (13.69% ± 11.88, n=16, P<.0001). P16INK4A expression was observed in interstitial valve cells within all compartments proportional to the degree of fibrosis and did not correlate with age, severity of aortic stenosis, or P53 expression. Multiple linear regression analysis by backward elimination revealed P16INK4A expression was lower among statin users (P<.01). CONCLUSIONS: P16INK4A- expression is ubiquitous in calcified aortic valves and correlates with severity of tissue remodeling, suggesting a role of cellular senescence in the progression of CAVD. Further research is needed to identify possible treatment modalities as disease modifying agents for CAVD.

Repurposing of Anticancer Stem Cell Drugs in Brain Tumors.

Brain tumors in adults may be infrequent when compared with other cancer etiologies, but they remain one of the deadliest with bleak survival rates. Current treatment modalities encompass surgical resection, chemotherapy, and radiotherapy. However, increasing resistance rates are being witnessed, and this has been attributed, in part, to cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells that reside within the tumor bulk and have the capacity for self-renewal and can differentiate and proliferate into multiple cell lineages. Studying those CSCs enables an increasing understanding of carcinogenesis, and targeting CSCs may overcome existing treatment resistance. One approach to weaponize new drugs is to target these CSCs through drug repurposing which entails using drugs, which are Food and Drug Administration-approved and safe for one defined disease, for a new indication. This approach serves to save both time and money that would otherwise be spent in designing a totally new therapy. In this review, we will illustrate drug repurposing strategies that have been used in brain tumors and then further elaborate on how these approaches, specifically those that target the resident CSCs, can help take the field of drug repurposing to a new level.

Rhabdoid collecting duct carcinoma with lymphangitic carcinomatosis causing acute lethal chylopericardium.

Collecting duct carcinoma is a rare neoplasm of the kidney, accounting for only 1-2% of renal tumors. These tumors arise from the principal cells of the renal collecting ducts of Bellini. The majority of patients have lymph node involvement and metastases to lungs, liver, bone, adrenal glands, and brain. We present a case of a 48 year old woman who came to the hospital with a clinical presentation suspicious for pneumonia. One week later her symptoms aggravated. A CT chest and abdominal imaging showed bilateral pulmonary infiltrates, retroperitoneal lymphadenopathy, and left hydroureteronephrosis. She expired after developing acute respiratory failure. An autopsy was performed which revealed chylopericadium of 150 cc; bilateral reticular pattern on the surfaces of the lungs; neck, mediastinal and retroperitoneal lymphadenopathy, and a 5.1 cm left kidney mass located in the mid portion medulla. The kidney tumor was a rhabdoid collecting duct carcinoma. The lungs showed diffuse subpleural lymphangitic spread of the carcinoma. We report a rare case of chylopericardium due to lymphangitic carcinomatosis from a 5.1 cm rhabdoid collecting duct carcinoma not suspected clinically or radiologically. This case highlights the importance of performing autopsies in an era when clinicians heavily rely on high-tech imaging diagnostic modalities.

An Unusual Case of Lower Extremity Clear Cell Hidradenocarcinoma.

Hidradenocarcinoma (HC) is a rare malignant sweat gland tumor with metastatic potential primarily located in the head, neck, and trunk. We present an unusual case of a large lower extremity Clear Cell HC managed with surgical resection and adjuvant locoregional radiation after excluding lymph node involvement.

Collision tumors of the lung: A case report of urothelial carcinoma metastasizing to renal cell carcinoma with heterotopic ossification.

Collision tumors are rare entities that consist of at least two or more histologically and ontologically distinct tumor types within the same organ. It is still not well understood how collision tumors form; yet, three main theories have been proposed to explain the pathogenesis, including the "random collision effect," "field cancerization," and "tumor-to-tumor carcinogenesis." Collision tumors have been encountered in various body organs, including the lung. They either consist of a metastasizing tumor colliding with primary cancer or distinct primary or metastatic cancers colliding together. Here, we describe a rare case of collision tumors of the lung that consists of two metastatic carcinomas, namely renal cell carcinoma and urothelial carcinoma of the bladder. We propose that the urothelial carcinoma disseminated into several pre-existing pulmonary metastases of renal cell carcinoma with heterotopic bone formation. The possible mechanisms underlying the development of this peculiar tumor are discussed.