Assessment of Pathology Domain-Specific Knowledge of ChatGPT and Comparison to Human Performance.

CONTEXT.­: Artificial intelligence algorithms hold the potential to fundamentally change many aspects of society. Application of these tools, including the publicly available ChatGPT, has demonstrated impressive domain-specific knowledge in many areas, including medicine. OBJECTIVES.­: To understand the level of pathology domain-specific knowledge for ChatGPT using different underlying large language models, GPT-3.5 and the updated GPT-4. DESIGN.­: An international group of pathologists (n = 15) was recruited to generate pathology-specific questions at a similar level to those that could be seen on licensing (board) examinations. The questions (n = 15) were answered by GPT-3.5, GPT-4, and a staff pathologist that recently passed their Canadian pathology licensing exams. Participants were instructed to score answers on a 5-point scale and to predict which answer was written by ChatGPT. RESULTS.­: GPT-3.5 performed at a similar level to the staff pathologist, while GPT-4 outperformed both. The overall score for both GPT-3.5 and GPT-4 was within the range of meeting expectations for a trainee writing licensing examinations. In all but one question, the reviewers were able to correctly identify the answers generated by GPT-3.5. CONCLUSIONS.­: By demonstrating the ability of ChatGPT to answer pathology-specific questions at a level similar to (GPT-3.5) or exceeding (GPT-4) a trained pathologist, this study highlights the potential of large language models to be transformative in this space. In the future, more advanced iterations of these algorithms with increased domain-specific knowledge may have the potential to assist pathologists and enhance pathology resident training.

Extensive Degenerative Change Masquerading Histomorphology in a Giant Cystic Gastrointestinal Stromal Tumor With Rare PDGFRA Mutation.

Gastrointestinal stromal tumors (GISTs) are the most frequent type of mesenchymal tumors of the gastrointestinal (GI) tract, and most of the time they acquire the mutation of special kinds of genes. GISTs may be familial or inherited and affect several family members of the family or can be sporadic. The risk of GIST is increased in people with mutations in the receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) genes. In this report, we present a case of a large GIST with extensive cystic and degenerative change in a 76-year-old female patient with a rare Asp842-His845 deletion mutation detected in PDGFRA exon 18, that required subtotal gastrectomy with en bloc resection.

Xanthogranulomatous Cholecystitis: A Diagnostic Challenge for Radiologists, Surgeons, and Pathologists.

Xanthogranulomatous cholecystitis (XGC) is a rare inflammatory disease of the gallbladder characterized by severe proliferative fibrosis and the accumulation of lipid-laden macrophages in areas of destructive inflammation. Misdiagnosis is highly usual, and its macroscopic appearance may often be confused with gallbladder carcinoma. Here we discuss the case of a 56-year-old male who presented in the emergency room with fever, chills, and nausea. The routine laboratory investigations were normal except for elevated white blood cell counts. Abdominal ultrasound showed borderline gallbladder wall thickening. However, after CT scan findings, the suspect diagnosis of acute cholecystitis with possible perforation was made and the cholecystectomy was performed. The definitive diagnosis was delayed until the final pathology result came as a surprise, and later confirmed the histologic diagnosis of XGC. We consider this an important case because of the histopathologic finding of fibrotic thickened gallbladder wall with abundant histiocytes and pericholecystic fat stranding along with perforation and extensive inflammatory changes in the right upper quadrant of the abdomen which is highly suggestive and indicative of XGC in comparison to gallbladder carcinoma (GC). All things considered, clinically and grossly XGC presents in a similar fashion as GC; histopathology confirmed the diagnosis of XGC.

Desmoplastic Trichoepithelioma: Histopathologic and Immunohistochemical Criteria for Differentiation of a Rare Benign Hair Follicle Tumor From Other Cutaneous Adnexal Tumors.

Desmoplastic trichoepitheliomas (DTEs) are benign cutaneous neoplasms that originate from the hair follicle and exhibit a preference for the facial region. This type of neoplasm is characterized by accelerated growth, with vigorous histologic and immunohistochemical features that may be confused with other skin cancers. Thus, the objective of this study is to establish a definitive diagnosis that can be widely used. This review was systematically carried out and includes case series and studies to establish valuable data that can be used for research. The articles were sought in PubMed, MEDLINE, and Google Scholar using the keywords "desmoplastic trichoepithelioma," "morphea basal cell carcinoma," "microcystic adnexal carcinoma," "syringoma," and "cutaneous breast carcinoma." From a total of 65 journal articles, we chose 42 studies describing the clinical features, etiology, histopathology, and immunohistochemical characteristics of tumors. After quality assessment, 10 studies were selected, representing the differentiating features among the four mentioned cutaneous tumors. The differential diagnosis of DTE also includes other cutaneous and follicular tumors. At present, there is no standardized grading system for trichogenic tumors, although several symptomatic terms have been offered. More recently, immunohistochemistry and histopathological studies support the differentiation between the above-mentioned cutaneous tumors. However, additional research needs to be conducted to obtain complete information regarding the specific distinct traits of the indicated cutaneous tumors.

Endometrioid Endometrial Carcinoma With Spindle Cells-Aberrant p16 and p53 Expression.

Endometrioid carcinoma is known for its diverse morphology and may pose a diagnostic dilemma when it presents with a spindle cell component. We present a case of a 65-year-old woman with postmenopausal bleeding. Physical examination showed a mass protruding from the external cervical os. The patient underwent biopsy followed by hysterectomy. Pathologic examination showed an endometrioid endometrial carcinoma with spindle cell differentiation arising in an endometrial polyp, which raised a variety of differential diagnoses. Prior reports of this tumor type showed nonaberrant immunohistochemical expression of p16 and p53. However, this case showed p16 and p53 overexpression indicating that there is a spectrum of these tumors.

A Recurrence of Bilateral Diffuse Sclerosing Lobular Hyperplasia of Breast: A Case Report.

Mammary sclerosing lobular hyperplasia is an uncommon benign fibroproliferative lesion of adolescent and young women, often of African American heritage with an incidence of ~3%. Patients generally complain of a palpable, painless, or slightly tender and well-defined lump in breast. Very rarely, this lesion may be bilateral and diffuse. The definitive diagnosis of sclerosing lobular hyperplasia requires histopathologic evaluation. Here, we describe a case of diffuse sclerosing lobular hyperplasia in a 29-year-old African American woman that required bilateral mastectomy and recurred bilaterally requiring second resections. This appears to be the first report of this phenomenon.

Metastatic intestinal adenocarcinoma to a lymph node involved by follicular lymphoma: The importance of looking beyond the apparent.

Composite tumors consisting of follicular lymphoma (FL) and colorectal or small intestinal adenocarcinoma are exceedingly rare, with only four cases published in the literature, to the best of our knowledge. While in most of these cases the clinical prognosis seems to be determined by the adenocarcinoma, at least one patient has shown rapid and aggressive progression of the FL. Here we report on a 62 year-old male with colonic adenocarcinoma metastatic to a retroperitoneal lymph node involved by FL, which illustrates the importance of carefully examining the histomorphology of lymphoid elements in surgical specimens.

Tear fluid extracellular DNA: diagnostic and therapeutic implications in dry eye disease.

PURPOSE: To determine the abundance of extracellular DNA (eDNA) in tear fluid of patients with dry eye disease (DED) and to report clinical outcomes after DNase I eyedrops use to reduce excessive tear fluid eDNA. METHODS: Tear fluid was collected from healthy control subjects and patients with DED. The eDNA abundance was determined with the PicoGreen dye assay. The DED symptoms and clinical signs were recorded and correlated with eDNA abundance. Two patients with DED having excessive eDNA in tear fluid were treated with DNase I eyedrops. RESULTS: The PicoGreen dye assay measures tear fluid eDNA abundance after a 2-minute incubation time. With longer incubations, admixed cells also contribute to eDNA measurements. The mean (SE) eDNA abundance in healthy control subjects' tear fluid was 1.4 (0.2) µg/mL. The mean (SE) eDNA abundance in tear fluid of patients with nonautoimmune DED, autoimmune DED, and graft versus host disease was significantly higher: the values were 2.9 (0.6), 5.2 (1.2), and 9.1 (2.3) µg/mL, respectively (P < 0.05). In most of these patients, the PicoGreen dye kinetic assay of tear fluid showed an increase in fluorescence signal due to the presence of viable cells in tear fluid. Tear fluid eDNA had the best correlation with corneal Rose Bengal staining (r = 0.55). Treatment of patients having DED with DNase I eyedrops reduced eDNA abundance, abrogated signal increase, and improved comfort. CONCLUSIONS: Excessive eDNA is present in tear fluid of patients with dry eyes. A novel therapeutic approach for managing DED may be to measure eDNA abundance in tear fluid with the PicoGreen dye assay and reduce excessive amounts with DNase I eyedrops.

Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease.

PURPOSE: We determined whether nucleases are deficient in the tear fluid of dry eye disease (DED) patients, and whether this causes extracellular DNA (eDNA) and neutrophil extracellular trap (NET) accumulation in the precorneal tear film, thus causing ocular surface inflammation. METHODS: Exfoliated cells adhered to Schirmer test strips were collected on glass slides, and immunofluorescence confocal microscopy was used to evaluate neutrophils, eDNA, NETs, and their molecular components. Similar experiments were performed with mucoid films collected from the inferior conjunctival fornix or bulbar conjunctiva. We used quantitative PCR to evaluate eDNA signaling pathways and inflammatory cytokine expression. We also determined the amount of ocular surface eDNA and evaluated tear fluid nuclease activity. RESULTS: eDNA, NETs, and neutrophils were present on the ocular surface in DED patients and abundant in mucoid films. NETs consisted of eDNA, histones, cathelicidin, and neutrophil elastase. Tear fluid nuclease activity was decreased significantly in DED patients, whereas the amount of eDNA on the ocular surface was increased significantly. Expression of genes downstream of eDNA signaling, such as TLR9, MyD88, and type I interferon, as well as the inflammatory cytokines interleukin-6 and tumor necrosis factor-α, was significantly increased in DED patients. CONCLUSIONS: Extracellular DNA production and clearance mechanisms are dysregulated in DED. Nuclease deficiency in tear fluid allows eDNA and NETs to accumulate in precorneal tear film, and results in ocular surface inflammation. These findings point to novel therapeutic interventions in severe DED based on clearance of eDNA, NETs, and other molecular components from the ocular surface.

Neurotrophins and nerve regeneration-associated genes are expressed in the cornea after lamellar flap surgery.

PURPOSE: To determine the in vivo expression of neurotrophins (NTs) and nerve regeneration-associated genes (RAGs) after surgically creating a hinged lamellar corneal flap in thy1-YFP mice. METHODS: Lamellar corneal flaps with multiple hinges were created in thy1-YFP mice. Mice were killed at weeks 2, 4, and 8. Quantitative polymerase chain reaction was performed to determine the expression of NTs and RAGs in the corneas after lamellar transection. Nerve growth factor (Ngf), brain-derived neurotrophic factor (Bdnf), glial cell-derived neurotrophic factor (Gdnf), neurotrophin 3, neurotrophin 5, small proline-rich repeat protein 1A (Sprr1a), growth-associated protein 43 (Gap43), and beta III tubulin (Tubb3) gene expressions were analyzed. Whole-mount confocal immunofluorescence and Western analyses were performed for localization and abundance of robustly expressed genes. RESULTS: Sprouts of fine YFP-positive fronds emanating from transected (injured) nerve bundles were seen in the flap area at 2 weeks onward. Bdnf and Sprr1a were robustly and significantly expressed at 2 weeks postoperatively (>2-fold increase in expression; P<0.05). Bdnf localized to thy1-YFP+ cells in operated corneas. Sprr1a localized to corneal epithelial cell membranes. At 8 weeks, none of the NTs and RAGs had increased expression. Bdnf (ρ=0.73, P=0.001) and Sprr1a (ρ=0.76, P=0.001) showed a significant positive correlation with beta III tubulin. CONCLUSIONS: The neurotrophin Bdnf and RAG Sprr1a are robustly and significantly expressed during corneal nerve regeneration in vivo.

Semaphorin 7a links nerve regeneration and inflammation in the cornea.

PURPOSE: We determined Semaphorin 7a (Sema7a) localization and abundance in naive corneas and in corneas after nerve-transecting lamellar flap surgery, and determined the effect of Sema7a supplementation on corneal nerve regeneration and inflammation. METHODS: Immunolocalization and Western blot analyses were performed to evaluate the abundance of Sema7a in naive corneas and corneas undergoing nerve regeneration after lamellar corneal surgery in thy1-YFP+ neurofluorescent mice. We used compartmental cultures of dissociated trigeminal ganglion cells to determine the effect of Sema7a exposure on neurite outgrowth in vitro. Finally, a Sema7a pellet was implanted under the corneal flap after lamellar transection surgery to determine the neuronal and inflammatory effects of Sema7a supplementation in vivo. RESULTS: Sema7a was expressed in the corneal epithelium and stromal keratocytes, but was more abundant in the epithelium (74.3%) compared to the stroma (25.7%, P = 0.02). Sema7a expression was increased significantly in the cornea after lamellar corneal surgery and was localized to stromal cells near the regenerating nerve fronds. Exposure of trigeminal neurites to Sema7a (20 nM) in the side compartment increased neurite length significantly. The implanted Sema7a pellet increased significantly YFP+ inflammatory cell influx into the cornea as well as increased corneal nerve length. CONCLUSIONS: Sema7a is expressed constitutively in the cornea, and potently stimulates nerve regeneration and inflammatory cell influx. Therefore, this immune semaphorin links nerve regeneration and inflammatory processes in the cornea.

Corneal neurotoxicity due to topical benzalkonium chloride.

PURPOSE: The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. METHODS: Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. RESULTS: BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). CONCLUSION: Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous tear production.

Cyclosporine immunomodulation retards regeneration of surgically transected corneal nerves.

PURPOSE: To determine whether immunomodulation with cyclosporine (CsA) affects reinnervation after surgical transection of stromal nerves. METHODS: Thy1-YFP+ neurofluorescent mice underwent lamellar corneal surgery and 3 days later, received artificial tears or CsA eye drops for 6 weeks. Serial in vivo wide-field stereofluorescent microscopy was performed to determine changes in nerve fiber density (NFD). Real-time quantitative PCR was performed to determine the expression of neurotrophins and cytokines (IL6 and TNF-α). Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether CsA directly affects neurite outgrowth. RESULTS: Yellow fluorescent protein (YFP)-positive cells significantly increased at 3 and 7 days after surgery. The number of YFP-positive cells in the cornea was significantly lower in the CsA group than that in the control group. The percentage increase in NFD between 2 to 6 weeks was greater in the control group (80% ± 10%, P = 0.05) than that in the CsA group (39% ± 21%). The CsA group also exhibited lower expression of IL6 and TNF-α (P = 0.01). In compartmental culture experiments, neurite outgrowth toward side compartments containing CsA was significantly less (2.29 ± 0.4 mm, P = 0.01) than that toward side compartments containing vehicle (3.97 ± 0.71 mm). CONCLUSIONS: Immunomodulation with CsA reduces the expression of cytokines (IL6) in the cornea and retards regenerative sprouting from transected corneal stromal nerve trunks. In addition, CsA has a direct growth inhibitory action on neurites as well.