bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative revision of the Lygodactylus gutturalis (Bocage, 1873) complex unveils extensive cryptic diversity and traces its evolutionary history
Authors: Lobón-Rovira Javier , Bauer Aaron M , Vaz Pinto Pedro , Trape Jean-Francois , Conradie Werner , Kusamba Chifundera , Júlio Timóteo , Cael Garin , Stanley Edward L , Hughes Daniel F , Behangana Mathias , Masudi Franck M , Pauwels Olivier S G , Greenbaum Eli
Published: September 2023

Lygodactylus is the most speciose gekkonid group in Africa, with several additional, candidate species already identified from previous studies. However, in mainland Africa, several groups remain only partially resolved, and there are several taxonomic inconsistencies. Lygodactylus gutturalis was described from Guinea-Bissau in the 1870s and since then, the species has been recorded from West to East Africa, and it is widely distributed through different biomes and ecoregions. However, this taxon has never been studied in detail. In this work, we use an integrative approach, including molecular phylogenetic analysis, morphometrics, skull osteology, and biogeography to provide the first systematic revision of the L. gutturalis species complex. The L. gutturalis complex is a subgroup within the L. picturatus group and includes nine well-differentiated species. We elevate Lygodactylus gutturalis dysmicus to full species status, recognize Lygodactylus depressus as the sister species to L. gutturalis, describe five new species (Lygodactylus kibera sp. nov., Lygodactylus karamoja sp. nov., Lygodactylus mirabundus sp. nov., Lygodactylus leopardinus sp. nov., and Lygodactylus gamblei sp. nov.), and propose an additional candidate species that requires further research. Also, in order to shed light on some taxonomic inconsistencies between the L. gutturalis and Lygodactylus angularis groups, we revisit the L. angularis group, within which we elevate Lygodactylus angularis heeneni and Lygodactylus angularis paurospilus to full species status. The L. gutturalis subgroup diversified during the Late Miocene (between 5–15 Mya), probably as a consequence of multiple vicariant events driven by the expansion of the African savannahs and the establishment of climatic refugia.
Prolidase Deficiency Causing Recalcitrant Leg Ulcerations in Siblings
Authors: Hajjar Nancy , Kabbani Mariam , Tannous Rim , Lebre Anne-Sophie , Megarbane Andre , Minari Afaf , El Sayed Fouad
Published: September 2023

Prolidase deficiency (PD) is a rare autosomal recessive genodermatosis with variable clinical manifestations. It results from a mutation in the peptidase-D gene that leads to abnormal activity of the prolidase enzyme, an important player in collagen catabolism. The authors report the case of two siblings presenting with dysmorphic features, disturbed blood panel, and recalcitrant leg ulcerations of several years’ duration. Sequencing of the 15 exons and of the intron/exon junction regions of the peptidase-D gene revealed the presence of a homozygous pathogenic variant c.549-1G > A. An ointment with 5% proline and 5% glycine was compounded, and the patients were instructed to apply it once daily. A follow-up visit after 8 months revealed partial improvement of the ulcerations starting from the third month of treatment. These authors hope this case report sheds light on this disease and recommend it be incorporated into the differential diagnoses of chronic leg ulcerations, particularly those starting at a young age.
Case Review: Gastric-Type Adenocarcinoma of the Uterine Cervix and Precursor Lesions
Authors: Park Kay J.
Published: September 2023

A case of gastric-type endocervical adenocarcinoma that was originally diagnosed as possibly of endometrial or pancreatobiliary/upper gastrointestinal tract origin is reported. This report reviews the pertinent medical literature, differential diagnoses, etiology, and pitfalls of this disease, as well as use of immunohistochemistry and human papillomavirus (HPV) testing in establishing the diagnosis. The morphology of these tumors can range from extremely well differentiated (minimal deviation adenocarcinoma) to poorly differentiated, and therefore, the differential diagnosis can be quite varied. On one end of the spectrum, the tumor can be difficult to differentiate from benign endocervical glands, whereas at the other end, it can be difficult to determine the origin of the tumor. Because these tumors are not associated with HPV infection, the use of ancillary studies such as p16 can be misleading, and these may not be detected on standard Papanicolaou cytology with HPV screening. Molecular testing was also performed in this case with a TP53 hotpot mutation detected, along with mutations in ELF3 and PTPRS.
Metastatic Adenocarcinoma to the Uterine Cervix Versus Primary Cervical Adenocarcinoma
Authors: Djordjevic Bojana , Busca Aurelia , Parra-Herran Carlos
Published: September 2023

Adenocarcinoma metastases to the cervix can originate from the endometrium, the upper müllerian tract, or from extramüllerian sites such as the gastrointestinal and pancreatobiliary tract, bladder, breast, lung, or even the salivary gland. In some cases, the metastatic lesions have signet-ring morphology, infiltrative pattern, and/or extensive lymphovascular spread. In others, however, the distinction between a primary cervical lesion and a metastasis to the cervix is more challenging because metastases may mimic endocervical adenocarcinoma in situ by colonizing the native endocervical mucosa through intraepithelial spread. Careful morphologic interpretation, combined with immunohistochemistry, human papillomavirus molecular testing, and clinical correlation, is required in order to arrive at the correct diagnosis.
Accurate Assessment of Histologic Parameters That Impact Lung Cancer Staging: Implications for the American Joint Committee on Cancer Eighth Edition TNM Classification
Authors: Butnor Kelly J.
Published: September 2023

The eighth edition of the American Joint Committee on Cancer TNM Classification represents a paradigm shift in lung cancer staging. Some staging parameters, such as the visceral pleural invasion, have not changed. Others are a significant departure from the prior edition, including tumor size used to assign T category, which for the first time is based solely on the invasive component, excluding any lepidic component. Understanding how to assess these histologic parameters will allow pathologists to contribute to the improved care of lung cancer patients through accurate pathologic staging.
Pathologic Staging of Colorectal Adenocarcinoma: Changes and Updates in the American Joint Committee on Cancer (AJCC) 8th Edition and College of American Pathologists' Cancer Protocol
Authors: Kakar Sanjay
Published: September 2023

The eighth edition of the AJCC Cancer Staging Manual has been published, and the new staging schemes will be applicable in 2018. The College of American Pathologists has also released an updated protocol incorporating these changes. While the overall T and N categories are similar to the seventh edition, the definitions of intramucosal adenocarcinoma, T4a category, and tumor deposits have been made more precise. The category of M1c has been created for peritoneal metastasis because of its worse outcome. In the College of American Pathologists protocol, tumor budding and venous invasion have been incorporated as recommended (optional) elements, the scoring of tumor regression has been updated, and the importance of screening for microsatellite instability/mismatch repair proteins has been emphasized. This review provides a brief description and rationale for these changes and updates.
Pure Red Cell Aplasia Due to T-Cell Large Granular Lymphocytic Leukemia After Hematopoietic Stem Cell Transplantation
Authors: Rangan Aruna , Oliveira Jennifer L. , Jevremovic Dragan , Morice William G. , Chen Dong , Shi Min
Published: September 2023

Although reactive polytypic large granular lymphocyte (LGL) expansions after hematopoietic stem cell transplant (HSCT) due to viral infection are common, T-cell large granular lymphocytic leukemia (T-LGLL) is extremely rare and usually clinically indolent and requires no treatment in the post-HSCT setting. In contrast, here we present a case of post-HSCT donor-derived T-LGLL that led to pure red cell aplasia with severe patient morbidity. After diagnosis, the patient received immunosuppressive treatment with a dramatic response and has been transfusion independent for more than a year. To our knowledge, this is the first case of a post-HSCT T-LGLL with a documented significant adverse clinical impact requiring and responding to therapeutic intervention. It underscores the importance of recognizing such a rare entity in posttransplant patients.
Ultrasound-Guided Fine-Needle Aspiration Practice Patterns
Authors: Heller Howard T. , Cibas Edmund S. , Kraft Adele O. , Jiang Xiaoyin “Sara” , Foo Wen-Chi , Sanchez Miguel A. , Powers Celeste N.
Published: September 2023

How ultrasound-guided fine-needle aspiration (USFNA) is performed in the United States varies considerably among institutions. The critical role of the cytopathologist for diagnosis is indisputable, although the degree of collaboration with other specialties and the physical setting where the procedure is performed are highly individualized, as is the degree to which the cytopathologist takes an active role in performing the biopsy. We highlight the practice patterns at 4 health centers in the United States. At 1 medical center, USFNAs are performed using a team approach: the aspiration is performed by a cytopathologist or trainee but is guided by a radiologist. In the remaining 3 medical centers, many USFNAs are performed without radiology assistance, with minor differences related to scheduling, personnel involved, and results reporting policies. All 4 medical centers report favorable patient and provider satisfaction. In conclusion, a variety of methods, all targeted to optimizing patient care and rapid diagnosis, work well and are generally well received by the physicians who refer their patients for care.
Creating Custom Phantoms for Ultrasound-Guided Fine-Needle Aspiration Biopsy Training
Authors: Jug Rachel , Jiang Xiaoyin “Sara”
Published: September 2023

Ultrasound-guided fine-needle aspiration (US-FNA) is superior to conventional fine-needle aspiration biopsies and when performed by cytopathologists yields higher diagnostic rates than when performed by nonpathologists. Ultrasound-guided fine-needle aspiration allows operators to perform targeted biopsies while avoiding critical nearby structures, decreasing the risk of procedural complications. Traditionally, cytopathology training programs have purchased costly commercial phantom models on which to train residents and fellows and provide opportunities for cytopathologists to practice their US-FNA technique. While phantoms are effective training tools, they are sold by several vendors at well over $1000 and have limited life spans as with continued use needle track marks obscure the ultrasound's view of practice targets. We developed and tested 2 cost-effective and easy-to-make recipes for creating your own US-FNA phantoms in-house. The first recipe features a gelatin-based phantom that can be made from ingredients available at any local grocery store. The second recipe for a silicon-based phantom is more durable but requires some ingredients that may be purchased online or at specialty costume shops. Finally, we share ideas and directions for making target lesions to be placed inside your phantoms and invite readers to harness their creativity to customize these phantom recipes to suit their practices' and trainees' needs.
Extensive Intravascular Thyroid Vein Extension in Follicular Thyroid Carcinoma: Ultrasound Clues
Authors: Kraft Adele , Prasad Uma
Published: September 2023

The identification of intravascular tumor thrombi in thyroid at the time of fine-needle aspiration is important as it is, by definition, a diagnosis of malignancy. While ultrasound findings of tumor thrombi in the great veins of the neck have been well described, thrombi in the thyroid veins can be very difficult to detect and have been seldom reported. This case study, with extensive thyroid vein tumor involvement, provides clues for raising the possibility of a malignant process at the time of ultrasound-guided FNA, by correlating the pathology findings with the ultrasound images.
Hyperbilirubinemia in a Hepatitis C Virus Patient After Liver Transplantation
Authors: Tondon Rashmi , Stashek Kristen M.
Published: September 2023

Fibrosing cholestatic hepatitis C virus is a rare, cholestatic hepatitis that can occur in the setting of immunosuppression or after transplantation in individuals with active hepatitis C infection. Its onset is heralded by hyperbilirubinemia and rapidly progresses to graft failure without treatment. It is characterized histologically by ballooning hepatocyte degeneration, bile duct proliferation, cholestasis, and perisinusoidal fibrosis. It is important to distinguish fibrosing cholestatic hepatitis from other common causes of hyperbilirubinemia in the posttransplant setting, including biliary obstruction and acute cellular rejection.
Budd-Chiari Syndrome: What Pathologists Need to Know About Hepatic Venous Outflow Obstruction
Authors: Pittman Meredith E.
Published: September 2023

Hepatic venous outflow obstruction, known as Budd-Chiari syndrome, is a rare but significant cause of hepatic dysfunction. Worldwide, the most common cause of hepatic venous outflow obstruction is thrombosis of the hepatic veins and/or inferior vena cava secondary to an inherited or acquired hypercoagulable state (eg, factor V Leiden deficiency). Depending on the extent and acuity of the thrombosis, patients with Budd-Chiari syndrome may present in acute liver failure or as chronic compensated cirrhosis; almost all will have the classic (but nonspecific) pairing of abdominal pain and ascites. Histologic findings in the liver also vary according to the time course and magnitude of thrombosis and can range from zone 3 congestion to established cirrhosis. The cases reported herein demonstrate 2 variations of Budd-Chiari syndrome encountered in the daily practice of pathology. The aims of this review were to examine the clinical, radiological, and histologic features of Budd-Chiari syndrome and to discuss the differential diagnosis based on the observed histologic pattern.
A Rare Case of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in the United States
Authors: De Michele Simona , Vittorio Jennifer M. , Thomas Tiffany , Diaz George A. , Lefkowitch Jay H. , Lagana Stephen M.
Published: September 2023

We describe the case of a 9-week-old female infant of Ashkenazi Jewish descent who presented with failure to thrive, vomiting, and persistent jaundice. Laboratory tests showed positive urine reducing substances as well as an abnormal amino acid profile, with increased arginine, threonine, methionine, tyrosine, lysine, and grossly elevated citrulline levels. Liver biopsy demonstrated the presence of cholestatic hepatitis with mixed steatosis and siderosis. Based on the aforementioned findings, a preliminary diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency was made. This diagnosis was later confirmed by molecular testing. Neonatal intrahepatic cholestasis caused by citrin deficiency is typically seen in infants of East Asian descent, and to the best of our knowledge, this is the first reported case in an American infant of Ashkenazi Jewish descent.
A Composite Lymphoma Consisting of a Mantle Cell Lymphoma and a Peripheral T-Cell Lymphoma: A Rare Case With Literature Review
Authors: Katsushima Hiroki , Nakajima Shinji , Takagawa Masanori , Fukuhara Noriko , Ichikawa Satoshi , Itakura Yuko , Harigae Hideo , Ichinohasama Ryo
Published: September 2023

A composite lymphoma (CL) is defined as 2 or more morphologically and immunophenotypically distinct lymphomas or lymphoid neoplasms that occur in the same organ or tissue. Many types of CL have been described in the literature, including 52 cases of CL with a component of mantle cell lymphoma (MCL) and only 2 cases of CL consisting of MCL and T-cell lymphoma. We hereby present a case of CL consisting of MCL and peripheral T-cell lymphoma, not otherwise specified. Morphologic features and flow cytometry analysis were both instrumental in the diagnosis of CL. In addition, we reviewed 52 reported cases of CL with MCL as a component. We found that the proliferation patterns of MCL have a relationship with the other component of the CL. We also found that many patients with CL had a history of lymphoproliferative disorders including lymphomas; this was observed in 9 of 52 cases, including 5 cases of MCL and 2 cases of another component of CL. This rate (approximately 17%) is relatively high and should not be ignored.
Endometrial Stromal Sarcoma With High-Grade Morphology and a JAZF1 Gene Rearrangement Presenting as Colonic and Cardiac Metastases: A Case Report and Review of the Literature
Authors: Jenkins Taylor M. , Cooper Kumarasen , Carolina Reyes M. , Deshpande Charuhas , Staats Paul N. , Schwartz Lauren E. , Stashek Kristen M.
Published: September 2023

Endometrial stromal tumors are a heterogeneous group of tumors with varied histologies and molecular alterations. JAZF1 rearrangements are typically characteristic of low-grade lesions, high-grade lesions usually harbor YWHAE alterations, and undifferentiated uterine sarcomas commonly present with complex karyotypes. We report a case of an endometrial stromal sarcoma with a JAZF1 gene rearrangement by fluorescence in situ hybridization and high-grade cytology presenting as cardiac and colonic metastases, in a patient with a remote history of hysterectomy for to “leiomyomas.”
Follicular Adenoma of the Thyroid With Spindle Cell Metaplasia Mimicking Insular Thyroid Carcinoma and Lacking Thyroglobulin Expression
Authors: Burke Allen , Staats Paul
Published: September 2023

We report a case of a well-encapsulated thyroid adenoma with areas of spindle cell metaplasia mimicking insular or poorly differentiated growth pattern. Emphasis on overall features, especially encapsulation and lack of invasion, is critical in the evaluation of thyroid neoplasms. In this example, there was loss of thyroglobulin expression, which to date has not been reported in spindled metaplasia but was not considered diagnostically relevant in the face of low proliferative activity and lack of mitotic figures.
Nonneoplastic Mimics of Appendiceal Mucinous Neoplasms
Authors: Misdraji Joseph
Published: September 2023

With the widespread acceptance of the term low-grade appendiceal mucinous neoplasm (LAMN) for relatively bland mucinous tumors of the appendix with pushing invasion and a propensity to disseminate to the peritoneal cavity, there has been increasing concern among pathologists of overlooking one of these tumors when an appendix shows extrusion of mucin into the wall or onto the serosa. The increased awareness of LAMN and its histologic features has caused some benign entities to be misinterpreted as LAMN based largely on the presence of mucin extrusion and hyperplastic and reactive appendiceal mucosa. The misinterpretation of some of these mimics as LAMN can have profound clinical consequences for patients, in terms of both overtreatment and anxiety. In this review, the most common nonneoplastic mimics of LAMN are reviewed. The most common of these mimics is ruptured diverticular disease of the appendix, which is frequently mistaken for ruptured LAMN. Retention mucoceles of the appendix can also cause confusion with LAMNs. Finally, a rare but curious form of endometriosis with intestinal metaplasia that occurs largely in the cecum and appendix can histologically mimic a mucinous neoplasm of the appendix.
Gastrointestinal Stromal Tumors—A Case Report With Review and Discussion of Updates
Authors: Barbieri Andrea Lynne , Jain Dhanpat
Published: September 2023

There has been tremendous growth in the understanding of gastrointestinal stromal tumors in the last 2 decades, particularly with regard to molecular classification. The role of the pathologist in appropriately assessing these tumors is more important than ever.
Primary Mesothelioma of the Liver: A Case Report
Authors: Wong Serena L. , Das Gargi , Cha Charles , Klimstra David S. , Jain Dhanpat
Published: September 2023

Primary hepatic mesotheliomas are very rare with only a few cases reported in the literature. Here we present a 55-year-old female with an 18 cm intrahepatic epithelioid mesothelioma with cystic changes who presented with non-specific abdominal pain and no prior history of exposure to asbestos. The tumor was resected with negative margins. The tumor was composed of islands of relatively monotonous epithelioid cells with extensive cystic degeneration. The nuclei were quite bland, round to oval with frequent grooves and inconspicuous nucleoli and minimal pleomorphism. Tumor necrosis was not seen. No keratinizaton or glandular differentiation was evident. The tumor background consisted of a rich inflammatory cell infiltrate composed of lymphocytes, plasma cells and histiocytes. The tumor was positive for mesothelial markers (calretinin, WT-1 and D2–40), keratins (CK5/6, CK7, CK19) and negative for a variety of other markers to exclude adenocarcinoma and other neoplasms. The patient is well and free of disease 8 years following the surgical resection.
Gastric Epithelial Carcinogenesis: From Atrophic Gastritis, Intestinal Metaplasia, and Dysplasia to Invasive Adenocarcinoma
Authors: Bosch Dustin E. , Truong Camtu D. , Yeh Matthew M.
Published: September 2023

Atrophic gastritis and intestinal metaplasia, often in the setting ofHelicobacter pyloriinfection, are associated with higher risk of gastric adenocarcinoma. According to the Correa model, the pathway of gastric carcinogenesis is triggered by chronic inflammation, which leads to atrophic gastritis, intestinal metaplasia, gastric dysplasia, and gastric carcinoma. Histopathologic assessment of atrophic gastritis suffers from low interobserver concordance, but staging with the Operative Link for Gastritis Assessment system effectively stratifies risk of gastric carcinoma. Intestinal metaplasia is a more highly reproducible diagnosis and can be classified with multiple systems including the Operative Link for Gastric Intestinal Metaplasia. Gastric epithelial dysplasia and invasive carcinoma are most commonly classified using the Vienna system among Western countries. The 2 tiers of dysplasia (low and high grade) are distinguished by severity of cytologic atypia, complexity of glandular architecture, loss of nuclear polarity, and degree of mitotic activity. However, grading of dysplasia on biopsy specimens suffers from high interobserver variability, as well as relatively poor correlation to Vienna system classification on subsequent resections. Intramucosal carcinoma is distinguished from high-grade dysplasia by neoplastic invasion into the lamina propria or muscularis mucosae. Grade of intraepithelial neoplasm and depth of invasive carcinoma remain central to guiding treatment decisions, while clinical approaches to surveillance and therapy continue to evolve.
Transformed Nodular Lymphocyte-Predominant Hodgkin Lymphoma: Histologic Features and Relationship to T-Cell/Histiocyte–Rich Large B-Cell Lymphoma
Authors: Alqaidy Doaa , Kallen Michael E. , Singh Zeba , Wilding Emily
Published: September 2023

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon variant of Hodgkin lymphoma, with a generally indolent course in low-stage presentations. Recurrences can demonstrate features of the diffuse variant, resembling T-cell/histiocyte–rich large B-cell lymphoma (THRLBCL). Transformation can additionally occur, either THRLBCL-like lesion or a diffuse large B-cell lymphoma (DLBCL). Transformation to DLBCL may be detected concurrently with NLPHL, prior to NLPHL, or years to decades later. The prognosis of such transformation is controversial, but thought to be worse than NLPHL and similar to that of de novo DLBCL. T-cell/histiocyte–rich large B-cell lymphoma–like transformation is histologically indistinguishable from primary THRLBCL, reflecting significant histologic and genetic overlap between NLPHL and THRLBCL. We present a patient with NLPHL and transformation to DLBCL at 7 years after initial diagnosis, who ultimately developed a therapy-related myeloid neoplasm. We review the histologic spectrum of transformed NLPHL, its relationship with THRLBCL, and recent developments in its molecular pathogenesis. Cases of transformation may prove valuable in understanding complex biologic relationships between a spectrum of overlapping lymphoma entities and may ultimately help refine therapy and improve prognosis.
Richter-like Pleomorphic Mantle Cell Lymphoma Composed of Epstein-Barr Virus–Positive Hodgkin-like Cells, a Diagnostic Challenge
Authors: Alvarez Jessica , Algashaamy Khaled , Tan Yaohong , Mackrides Nicolas , Peng Jing Hong , Byrnes John , Alderuccio Juan P. , Alencar Alvaro , Vega Francisco , Chapman Jennifer
Published: September 2023

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with distinctive clinicopathologic features including the presence of t(11;14)(q13;q32) in almost all cases. Histologically identifiable variants are well described. Most MCLs are the classic variant, although more aggressive variants including blastoid and pleomorphic exist. The pleomorphic variant is a morphologic subtype composed predominantly of large atypical lymphoid cells. This variant can arise de novo or occur in patients with previous history of MCL as result of disease progression and clonal evolution. Mantle cell lymphoma is characteristically Epstein-Barr virus (EBV) negative. Here, we present an extremely unusual case of pleomorphic MCL that arose in a 69-year-old man with a previous 10-year history of indolent chronic leukemia. This case was unusual and diagnostically challenging because the large and pleomorphic lymphoma cells were EBV positive and had Hodgkin-like morphologic features and only focal cyclin D1 expression. Fluorescence in situ hybridization studies confirmed the presence of the CCND1-IgH gene rearrangement. The disease was clinically aggressive, and the patient died 12 months after diagnosis. Epstein-Barr virus–associated MCL and large cell progressions of MCL are only rarely reported. The additional features we describe, including only focal expression of cyclin D1 and Hodgkin-like morphology, make this an even more unusual and therefore difficult to identify lymphoma. Importantly, this case raises the question as to whether MCL can have histopathologic progressions analogous to the well-established EBV-associated Hodgkin-like Richter transformations of chronic lymphocytic leukemia/small lymphocytic lymphoma.
Transformed Follicular Lymphoma: The Role of the Pathologist in Aiding Therapeutic Decision Making
Authors: Pasion Jeremiah , El Chaer Firas , Rapoport Aaron , Dahiya Saurabh , Koka Rima
Published: September 2023

Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma. Follicular lymphoma is generally an indolent disorder, and despite being incurable with standard chemotherapy, recent advances in treatment strategies have improved clinical outcomes and survival. Over time, FL could acquire additional genetic mutations and transform into diffuse large B-cell lymphoma, a more aggressive B-cell neoplasm, which markedly reduces survival. Treatment of transformed FL is based on combination chemotherapy and immunotherapy. Rituximab has changed the treatment landscape in FL. However, novel approaches to treatment of transformed FL are in development. Here, we present a case of FL with transformation to diffuse large B-cell lymphoma and review diagnostic modalities along with current and upcoming therapies, many of which require assessment of antigen expression patterns from the pathologist. In particular, we will highlight the role the pathologist plays in management decisions.
Spironolactone Bodies: An Interesting Pathological Phenomenon in Adrenal Aldosteronomas
Authors: Moore Edwina C. , Nguyen Jane , Magi-Galluzzi Cristina , Siperstein Allan
Published: September 2023

This is a case of a patient with Conn syndrome. We present a brief summary of his presentation, diagnostic work-up, operative management, and outcome. The association of spironolactone bodies (S bodies) with the use of spironolactone in patients with Conn syndrome is described. Furthermore, the incidence, pathophysiology, and histological characteristics or S bodies are reviewed. This case is educational as it provides a concise summary of the workup for adrenal aldosteronomas. Additionally, it highlights a rare and poorly understood pathological feature unique to this tumor type. Recognition of S bodies in a surgical specimen adds to diagnostic certainty and may avoid delay in pathological diagnosis or unnecessary investigations postoperatively.
Combined Erdheim-Chester Disease and Langerhans Cell Histiocytosis in the Lung: A Report of 2 Patients With Overlap Syndrome
Authors: Pires Yumay , Jokerst Clinton E. , Panse Prasad M. , Kipp Benjamin R. , Tazelaar Henry D.
Published: September 2023

Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are two rare diseases typically separated by clinical, radiologic, and histologic criteria. However, coexistence of both entities is rare, with fewer than 50 cases reported. Although there are reports of patients with LCH and ECD in the same organ, there have been no reported cases of the two diseases involving the lung. We report two cases of ECD-LCH “overlap syndrome” occurring in the lung. In both cases, the diagnoses were supported by typical immunohistochemical patterns, and in both cases, the BRAF V600E mutation was identified by next-generation sequencing and confirmed by droplet digital polymerase chain reaction. In neither case was either diagnosis suspected. The recognition of overlap histiocytoses is important. Although LCH and ECD may differ in treatment and prognosis, in some cases, such as the two patients reported here, they may have the same activating mutations and may be able to be treated with the same targeted therapy.
Bilateral Multifocal Warthin Tumors Mimicking Metastatic Papillary Thyroid Carcinoma: A Rare Case Posing a Diagnostic Challenge
Authors: Kulkarni Tanvee , Shah Snehal , Rane Swapnil , Mahajan Abhishek , Bal Munita , Vaish Richa , Patil Asawari
Published: September 2023

Warthin tumor is the second most common benign tumor of parotid gland. It rarely may be multifocal and occur at extraparotid sites, most common being the cervical lymph nodes. Fine-needle aspirate cytology is diagnostic in most cases of parotid Warthin tumors; however, in extraparotid sites, the diagnosis can be challenging. The difficulty can be further amplified if there is a synchronous lesion in a visceral organ on radiology, raising the suspicion of a metastatic carcinoma. We report an unusual diagnostically challenging case of synchronous, bilateral, multifocal intraparotid and extraparotid Warthin tumors mimicking a metastatic papillary thyroid carcinoma. We also highlight the usefulness of intraoperative consultation in guiding appropriate management in such cases.
Pitfalls and Traps in Neuropathology
Authors: Smith Michael Timothy , Bruner Evelyn T.
Published: September 2023

Impediments to making a correct diagnosis are avoided, and complex administrative efforts are used to make those impediments less frequent. There are quality control procedures, patient safety initiatives, and endless meetings attempting to lessen medical errors. Pitfalls and traps are encountered daily by pathologists, and most are avoided. Artifacts produce traps created by cautery, physical crush, thick sections, and drying and are well known. Appropriate deferral, recuts, stains, and collegial consultations aid in error avoidance in these instances. Neuropathology has some pitfalls and traps that are encountered infrequently especially in the low neuropathology case load environment. Those traps are unfamiliar and treacherous for the unwary pathologist. This review describes five cases each with its special trap.
Delayed Presentation of Sagittal Suture Craniosynostosis
Authors: Modi Rishi N. , Belza Caitlyn C. , Kamel George N. , McKee Ryan M. , Carbullido Mary K. , Gosman Amanda A.
Published: September 2023

Background

Sagittal craniosynostosis typically presents as dolichocephaly or less frequently as clinocephaly, a “saddle-shaped” phenotype. This project aimed to characterize clinically relevant differences between sagittal synostosis phenotypes and examine the etiology of the delay in presentation.

Methods

An institutional review board–approved retrospective review was performed from January 1999 to November 2018 at a single institution. Analyses examined correlations between subphenotype, time of presentation, minor suture fusion, developmental delay, and operative technique.

Results

One hundred sixty patients diagnosed with single-suture sagittal craniosynostosis were identified. A total of 30.6% had a saddle phenotype (n = 49) and 69.4% had dolichocephaly (n = 111). Patients with the saddle phenotype were more likely to present with a developmental delay and to have at least 1 minor suture fused than patients with dolichocephaly were. Patients with the saddle phenotype presented for surgery at an older age and were more likely to undergo open cranial vault repair, with increased blood loss, higher transfusion volume, and longer time.

Conclusions

This study highlights clinical differences in sagittal craniosynostosis phenotypes and shows that developmental delay is an initial presentation of the saddle phenotype. The saddle phenotype also correlated with fusion of the minor squamous and sphenoid sutures. The link between developmental delay and minor suture fusion was notable and should be explored with a larger sample size. Patients with saddle synostosis present for surgery at an older age than patients with dolichocephaly and therefore are more likely to receive open cranial vault repair, with a taxing intraoperative experience characterized by increased blood loss, increased transfusions, and longer operation time.
Analysis of Readmission and Complications After Repair of Orbital Fractures Using California's Office of Statewide Health Planning and Development Database
Authors: Chopra Christina S. , Neubauer Daniel C. , Hornacek Michael , Calvo Richard Y. , Segal Rachel , Reid Christopher M. , Martin Matthew J. , Gosman Amanda A.
Published: September 2023

Background

Orbital fractures represent one of the most common trauma-related facial fractures and may present with a variety of concomitant injuries. Many factors including age, associated diagnoses, and fracture complications are important in determining surgical candidacy. We used a statewide database to determine the prevalence of orbital fractures, rates of surgical repair during initial admission, and early patient outcomes.

Methods

A longitudinal analysis of patients with orbital fracture was performed using California's Office of Statewide Health Planning and Development patient discharge database for admissions occurring between January 2015 and December 2018.

Patients were identified using International Classification of Diseases, Tenth Revision codes. The primary risk factor was surgical management of orbital fractures. The primary outcomes of interest were readmission requiring surgical management and complications of the fracture. Survival models were developed to evaluate the risk of a repair at readmission adjusting for relevant covariates.

Results

Of the 67,408 facial fractures included in our study, 8.7% (n = 5872) were diagnosed with orbital fractures. Among this population, 18.4% (n = 1082) underwent surgical repair during their initial admission. Patients were primarily male (71.1%; n = 4,173) and presented in a nonurgent fashion (93.7%; n = 5501). Less than half (42.8%) of patients with an urgent presentation and 16.8% of patients with a nonurgent presentation underwent repair. Centers of Medicaid & Medicare Services guidelines dictated presentation classification. Repair was associated with a significantly higher survival outcome. Orbital fractures were more frequently repaired in the setting of concomitant zygomatic, nasal, and LeFort I–III fractures. Increased risk in complications was observed in all concomitant fracture groups, and there existed a decreased risk of postsurgical complications in these same cohorts.

Conclusions

Although most orbital fractures were managed nonoperatively, our analysis found that rates of repair for orbital floor, maxillary, and zygomatic fractures were greater than for other facial fractures. Concomitant fractures were associated with an increased hazard ratio for complications. Although low in prevalence overall, the most often observed postoperative complications in this population were diplopia, glaucoma, and blindness/low vision.
Elevation, drainage, and spatially heterogeneous vulnerability of tidal marshes to sea level rise
Authors: Qi Man , Gedan Keryn
Published: September 2023

Marsh plants regulate marsh surface elevation through organic matter accumulation and sediment capturing, thus feedback loops and relationships between vegetation and marsh elevation form the basis of numerical models that estimate and predict marsh vulnerability to Sea Level Rise (SLR). However, with interior portions of shallow-sloping microtidal marshes suffering much more extensive inundation relative to edge marshes, it is necessary to identify factors in addition to elevation that create spatial heterogeneity in flood vulnerability. Here we studied the influence of drainage on vulnerability of the marsh interior and the marsh edge. Specifically, we compared the deviation ofin situobserved hydrological metrics for surface (hydroperiod, daily inundation duration) and subsurface (soil saturation index, or SSI) soil levels of interior and edge marsh from expected values estimated using elevation and tidal regime alone. We further analyzed the bias that hydrological deviation introduced to marsh vulnerability estimation using growth response curves of typical marsh macrophytes to hydroperiod. We found that the water table fluctuation was attenuated from marsh edge to interior, which resulted in a higher sensitivity of interior marsh to elevation deficiency. At the brim of marsh collapse in the marsh interior, hydroperiod and SSI increased dramatically; they were 20-50% higher than at the same elevation at the marsh edge, which greatly reduces the window of opportunity for interior marsh plant communities to adapt to SLR. Our findings demonstrate the importance of drainage in explaining spatial patterns in vulnerability across the marsh platform, which should be considered in future empirical studies and numerical simulations to develop practical tools for coastal management.
Simultaneous Native Mass Spectrometry Analysis of Single and Double Mutants to Probe Lipid Binding to Membrane Proteins
Authors: Jayasekera Hiruni S. , Mohona Farhana Afrin , Ewbank Megan , Marty Michael T.
Published: September 2023

Lipids are critical modulators of membrane protein structure and function. However, it is challenging to investigate the thermodynamics of protein-lipid interactions because lipids can simultaneously bind membrane proteins at different sites with different specificities. Here, we developed a native mass spectrometry (MS) approach using single and double mutants to measure the relative energetic contributions of specific residues on Aquaporin Z (AqpZ) toward cardiolipin (CL) binding. We first mutated potential lipid-binding residues on AqpZ, and mixed mutant and wild-type proteins together with CL. By using native MS to simultaneously resolve lipid binding to the mutant and wild-type proteins in a single spectrum, we directly determined the relative affinities of CL binding, thereby revealing the relative Gibbs free energy change for lipid binding caused by the mutation. Comparing different mutants revealed that the W14 contributes to the tightest CL binding site, with R224 contributing to a lower affinity site. Using double mutant cycling, we investigated the synergy between W14 and R224 sites on CL binding. Overall, this novel native MS approach provides unique insights into lipid binding to specific sites on membrane proteins.
Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology
Authors: Leung Szi Kay , Jeffries Aaron R , Castanho Isabel , Bamford Rosemary A , Moore Karen , Dempster Emma L , Brown Jonathan T , Ahmed Zeshan , O’Neill Paul , Hannon Eilis , Mill Jonathan
Published: September 2023

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer’s disease (AD), a devastating neurodegenerative disorder involving the intracellular aggregation of hyperphosphorylated tau. We used long-read cDNA sequencing to profile transcript diversity in the entorhinal cortex of wild-type (WT) and transgenic (TG) mice harboring a mutant form of human tau. Whole transcriptome profiling showed that previously reported gene-level expression differences between WT and TG mice reflect changes in the abundance of specific transcripts. Ultradeep targeted long-read cDNA sequencing of genes implicated in AD revealed hundreds of novel isoforms and identified specific transcripts associated with the development of tau pathology. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of neuropathology. Our transcript annotations and a novel informatics pipeline for the analysis of long-read transcript sequencing data are provided as a resource to the community.
Differential evolution of cooperative traits in aggregative multicellular bacteriumMyxococcus xanthusdriven by varied population bottleneck sizes
Authors: Kalathera Jyotsna , Patel Vishwa , Pande Samay
Published: September 2023

Repeated population bottlenecks influence the evolution and maintenance of cooperation1,2. However, it remains unclear whether bottlenecks select all cooperative traits expressed by an organism or only a subset of them.Myxococcus xanthus, a social bacterium, displays multiple cooperative traits, including growth, predation, sporulation in multicellular fruiting bodies, and germination3–6. Using laboratory evolution experiment, we investigated the effect of repeated stringent versus relaxed population bottlenecks on the evolution of these four cooperative traits when they were all under selection. We found that only fruiting body formation and growth were positively selected under the stringent regimen, while the other two traits were negatively selected. The pattern was reversed in the relaxed regimen. Additionally, the relaxed regimen led to a significant increase in fitness when competed against ancestors across the entire lifecycle, whereas the stringent treatment did not change competitive fitness. Genomic analysis revealed that mutations in σ54interacting protein and DNA-binding response regulator protein are linked with the changes observed in stringent and relaxed regimens respectively. Further, similar trade-offs are also seen among natural populations ofM. xanthus. Overall, we demonstrate that different bottleneck sizes drive the evolution of lifecycles in distinct manners, driven by trade-offs between cooperative life history traits.
Bayesian analysis of resting-state temporal low-γ power in children with phonemic decoding deficits and certain comorbidities
Authors: Lasnick Oliver , Hancock Roeland , Hoeft Fumiko
Published: September 2023

Dyslexia (decoding-based reading disorder, or RD) is a common learning disorder affecting a large proportion of the population. One theory of the origins of reading deficits is a language network which cannot effectively ‘entrain’ to speech, with cascading effects on the development of phonological skills. Low-gamma (low-γ, 30-45 Hz) neural activity is thought to correspond to tracking at phonemic rates in speech. The main goals of the current study were to investigate temporal low-γ band-power during rest in a sample of children and adolescents with and without RD. We used a Bayesian statistical approach, which has become increasingly popular in the field for its ability to quantify the relative likelihood of competing hypotheses. We examined whether (1) resting-state temporal low-γ power was attenuated in the left temporal region in those with RD; (2) low-γ power covaried with individual performance in reading skills; (3) low-γ temporal lateralization was atypical in the group with RD. Results did not support the hypothesized effects of RD status and poor phonemic decoding ability on left hemisphere low-γ power or lateralization: post-hoc tests revealed that the lack of atypicality in the RD group was not due to the inclusion of those with comorbid attentional deficits. However, post-hoc tests also revealed a specific left-dominance for low-γ rhythms in the RDs only when participants with attentional deficits were excluded. We also observed an inverse relationship between phonemic decoding and left-lateralization in the controls, such that those with better decoding skills were less likely to show left-lateralization, contrary to our expectations. We discuss these unexpected findings in the context of prior theoretical frameworks on temporal sampling, and suggest that our null findings in resting-state EEG may reflect the importance of real-time language processing to evoke gamma rhythms in the phonemic range during childhood and adolescence.
Tracing endogenous proteins in living cells through electrotransfer of mRNA encoding chromobodies
Authors: Juncker Théo , Richert Ludovic , Masson Murielle , Chatton Bruno , Donzeau Mariel
Published: September 2023

Chromobodies made of nanobodies fused to fluorescent proteins are powerful tools for targeting and tracing intracellular proteins in living cells. Typically, this is achieved by transfecting plasmids encoding the chromobodies. However, an excess of unbound chromobody relative to the endogenous antigen can result in high background fluorescence in live cell imaging. Here, we overcome this problem by using mRNA encoding chromobodies. Our approach allows one to precisely control the amount of chromobody expressed inside the cell by adjusting the amount of transfected mRNA. To challenge our method, we evaluate three chromobodies targeting intracellular proteins of different abundance and cellular localization, namely lamin A/C, Dnmt1 and actin. We demonstrate that expression of chromobodies in living cells by transfection of tuned amounts of the corresponding mRNAs allows the accurate tracking of their cellular targets by time-lapse fluorescence microscopy.