Evaluating the diagnostic performance of a large language model-powered chatbot for providing immunohistochemistry recommendations in dermatopathology.

BACKGROUND: Large language model (LLM)-powered chatbots such as ChatGPT have numerous applications. However, their effectiveness in dermatopathology has not been formally evaluated. Dermatopathological cases often require immunohistochemical workup. Here, we evaluate the performance of a chatbot in providing diagnostically useful information on immunohistochemistry relating to dermatological diseases. METHODS: We queried a commonly used chatbot for the immunophenotypes of 51 cutaneous diseases, including a diverse variety of epidermal, adnexal, hematolymphoid, and soft tissue entities. We requested it to provide references for each diagnosis. All tests were repeated, compiled, quantified, and then compared with established literature standards. RESULTS: Clustering analysis demonstrated that recommendations correlated with tumor type, suggesting chatbots can supply appropriate panels. However, a significant portion of recommendations were factually incorrect (13.9%). Citations were rarely clinically useful (24.5%). Many were confabulated (27.2%). Prompt responses for cutaneous adnexal lesions tended to be less accurate while literature references were less useful. Reference retrieval performance was associated with the number of PubMed entries per entity. CONCLUSIONS: This foundational study suggests that LLM-powered chatbots may be useful for generating immunohistochemical panels for dermatologic diagnoses. However, specific performance capabilities and biases must be considered. In addition, extreme caution is advised regarding the tendencies to fabricate material. Future models intentionally fine-tuned to augment diagnostic medicine may prove to be valuable.

Bi-Layer nanoimprinting lithography for metal-assisted chemical etching with application on silicon mold replication.

This paper reports a new type of nanoimprinting method called Bi-layer nanoimprinting lithography (BL-NIL), which can work along with metal-assisted chemical etching (MaCE) for fabricating nanostructures on silicon. In contrast to conventional nanoimprinting techniques, BL-NIL adds an interposing layer between the imprinting resist layer and silicon substrate. After the standard imprinting process, dry etching was used to etch away the residual imprinting layer and part of the interposing layer. Finally, the remaining interposing layer was wet-etched using its remover. This innovative approach can ensure cleanliness at the metal/silicon interface after metal lift-off processes, and therefore guarantees the success of MaCE. By combining BL-NIL and MaCE, expensive silicon molds with sub-micrometer/nanometer-scale feature sizes can be easily replicated and preserved. This is important for the application of nanoimprinting technologies in industrial manufacturing.

Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling.

Acquisition of planar cell polarity (PCP) in epithelia involves intercellular communication, during which cells align their polarity with that of their neighbors. The transmembrane proteins Frizzled (Fz) and Van Gogh (Vang) are essential components of the intercellular communication mechanism, as loss of either strongly perturbs the polarity of neighboring cells. How Fz and Vang communicate polarity information between neighboring cells is poorly understood. The atypical cadherin, Flamingo (Fmi), is implicated in this process, yet whether Fmi acts permissively as a scaffold or instructively as a signal is unclear. Here, we provide evidence that Fmi functions instructively to mediate Fz-Vang intercellular signal relay, recruiting Fz and Vang to opposite sides of cell boundaries. We propose that two functional forms of Fmi, one of which is induced by and physically interacts with Fz, bind each other to create cadherin homodimers that signal bidirectionally and asymmetrically, instructing unequal responses in adjacent cell membranes to establish molecular asymmetry.

Reflectance confocal microscopic visualization of melanocytic bodies in the stratum corneum overlying acral lentiginous melanoma.

BACKGROUND: We present a case of RCM evaluation of ALM surgical margins demonstrating intracorneal melanocytic bodies overlying subsequently confirmed melanoma in situ by histopathology. CASE PRESENTATION: A 73-year-old male with a history of acral lentiginous melanoma (ALM) of the right great toe presented to our clinic for evaluation of positive surgical margins. The positive margin was localized for examination and subsequent biopsy with reflectance confocal microscopy (RCM) which allowed targeted re-resection of the area of concern. Three punch biopsies were obtained in the area of concern, which confirmed residual melanoma in situ. Immunostains confirmed the cellular remnants in the stratum corneum were melanocytic. To correlate the intra stratum corneum findings seen with confocal to the histopathology, a 3D rendering of a stack of images was used to demonstrate the location. DISCUSSION: Typically, acral surfaces are challenging to examine with RCM due to the limited ability of light to penetrate thickened stratum corneum; however, we observed unique cellular features with confocal. Scattered hyper-reflective pleomorphic cells consistent with melanocytes were observed in the stratum corneum, although the visualized underlying epidermis appeared normal. Confocal microscopy may aid in diagnosis and management of ALM, especially in the context of positive surgical margins.

Foreign body reaction toward hydrophilic polymer at the site of endovascular procedure: A report of two cases.

Hydrophilic polymer-coated devices have been increasingly utilized for various endovascular procedures, however not been without adverse effects. We report two cases of subacute cutaneous lesions on the neck encountered in our dermatology clinic. Histopathologic findings were significant for a nodular aggregate of epithelioid histiocytes and lymphocytes with numerous foreign body giant cells in the dermis. The granulomatous infiltrate was associated with an amorphous basophilic non-polarizable material. Further chart review reveals both patients receiving a central venous procedure in the past, thus attributing the hydrophilic polymers as the likely source of the foreign material found at the insertion site. Our cases contrast to the more commonly reported distal embolization by these hydrophilic polymer layers. We suspect the incidence of retained hydrophilic polymer at the site of prior endovascular procedures may be underreported in the literature with the more inconspicuous presentations. Therefore, retained foreign material should be considered by both treating physicians and dermatopathologists in presenting cases of lesions that occur at common sites of endovascular procedures.

Histologic Patterns of Cutaneous Metastases of Breast Carcinoma: A Clinicopathologic Study of 232 Cases.

ABSTRACT: Cutaneous metastasis may be the initial sign of internal malignancy but more often represents a late manifestation of widely disseminated disease. Breast carcinoma is the most common malignancy to metastasize to the skin. Although several studies have detailed the histopathologic patterns of cutaneous metastasis from internal malignancies, very little has been published regarding metastases of breast carcinoma to the skin. Furthermore, the histopathologic and clinical features observed in the cases of breast carcinoma with local skin involvement as opposed to cases exhibiting distant cutaneous metastases have not been adequately investigated. We have reviewed 232 cases of breast carcinoma with cutaneous metastases from 2 large institutions. All cases of carcinoma of the breast with involvement of the skin of the anterior chest wall were compared with those with distant cutaneous metastases. Two hundred thirty-two cases in 199 patients were included, of which 126 had skin involvement exclusively involving the ipsilateral anterior chest, and 106 had biopsy-proven distant cutaneous metastases. Twelve patients had both local and distal spread. Distant cutaneous metastases showed a predilection for the contralateral anterior chest wall area, followed by the head and neck, back, and abdomen. Histologically, most of the tumors presented in this series showed features of infiltrating ductal carcinoma. In both ipsilateral and distant metastases, the tumors demonstrated little change in histologic features from the primary lesion; however, the distant metastases showed a tendency to display more poorly differentiated features. The mean patient survival when cutaneous involvement was localized to the skin of the anterior chest wall was 23 months as compared with 20.6 months when distant sites were affected. A comparison of the clinicopathologic features of the patients presented in this series suggests that alternate biological mechanisms may apply for local and distant skin metastases from breast carcinoma.

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

Suprabasal acantholytic dermatologic toxicities associated checkpoint inhibitor therapy: A spectrum of immune reactions from paraneoplastic pemphigus-like to Grover-like lesions.

Checkpoint inhibitors (CPIs) restore the function of effector immunocytes to target and destroy cancer cells. Immune-related adverse events (irAEs) are a consequence of immune reactivation, with unpredictable inflammatory response, loss of self-tolerance, and development of autoimmunity. Adverse events from CPIs that present as dermatologic toxicities have diverse clinical and histopathologic features. CPI-associated dermatologic toxicities may exhibit histopathologic features of lichenoid dermatitis, bullous pemphigoid, and granulomatous/sarcoid-like reactions. Suprabasal acantholytic dermatologic toxicities associated with CPIs are particularly rare but represent an emerging histopathologic pattern and include lichenoid dermatitis with suprabasal acantholysis/vesicle formation to Grover disease (transient acantholytic dermatosis). Here, we report two patients who developed suprabasal acantholytic dermatologic toxicities during CPI therapy. One patient exhibited a CPI-associated autoimmune blistering disease with paraneoplastic pemphigus (PNP)-like features restricted to histopathology and immunofluorescence, while the other patient had Grover-like lesions. A review of the literature revealed a spectrum of suprabasal acantholytic dermatologic toxicities associated CPIs that may present as lichenoid dermatitis with acantholysis/vesicle formation, Grover-like eruptions, and lesions with PNP-like features restricted to histopathology and immunofluorescence. It is important for clinicians and pathologists to recognize the types of dermatologic toxicities associated with CPIs to direct appropriate therapeutic strategies.

Growth-associated protein 43 in differentiating peripheral nerve sheath tumors from other non-neural spindle cell neoplasms.

The malignant peripheral nerve sheath tumor is a relatively uncommon type of soft tissue sarcoma arising from a peripheral nerve or extraneural soft tissues and showing nerve sheath differentiation. The diagnosis of malignant peripheral nerve sheath tumor is one of the most challenging tasks in surgical pathology because of its uncommon type (5-10% soft tissue sarcomas), morphologic resemblance to other spindle cell neoplasms and lack of sensitive and specific immunohistochemical markers. The pathologic diagnosis is more straightforward in the clinical setting of neurofibromatosis-1, but problems are mainly centered on the non-neurofibromatosis-1 malignant peripheral nerve sheath tumors. To date, S100 protein is the most widely applied marker in the case of a suspected malignant peripheral nerve sheath tumor, yet its suboptimal sensitivity and its expression in other spindle cell neoplasms, including spindle cell melanoma, clear-cell sarcoma, leiomyosarcoma and monophasic synovial sarcoma, add to the diagnostic conundrum. Growth-associated protein 43 (GAP43), a membrane-associated phosphoprotein expressed in neuronal growth cones and Schwann cell precursors during neural development and axonal regeneration, was applied to a set of nerve sheath and non-nerve sheath spindle cell neoplasms. The findings in this study indicate that GAP43 is expressed in malignant peripheral nerve sheath tumors (n=18/21; 86%) and demonstrates a sensitivity superior to S100 protein (n=13/21; 62%). GAP43 is also positive in neurofibromas (n=17/18; 94%), schwannomas (n=11/12; 92%) and desmoplastic melanomas (n=7/10; 70%). In contrast, it is negative in the non-desmoplastic spindle cell melanomas (n=20/22; 91%). Of the other non-neural soft tissue sarcomas, GAP43 is non-reactive in most leiomyosarcomas (n=14/16; 88%) and clear-cell sarcomas (n=8/8), and only focally positive in monophasic synovial sarcomas (n=3/7; 43%). GAP43 is seemingly a highly sensitive marker for peripheral nerve sheath tumors and may serve as a useful diagnostic adjunct in the diagnosis of malignant peripheral nerve sheath tumor from other spindle cell neoplasms, including spindle cell melanoma.

Clinicopathologic correlation of dermatologic diseases in patients with darker pigmentation.

OBJECTIVES: Cutaneous diseases that disproportionately affect patients with darker pigmentation and their histologic features are historically understudied and undertreated. This review article aims to highlight the key clinical features, histopathology, and diagnostic pearls of several cutaneous diseases that commonly present in patients with darker pigmentation. METHODS: A literature search was conducted, and a list of cutaneous diseases that frequently affect patients with darker pigmentation was compiled. A group of experts expounded upon those that were most common or misdiagnosed according to scientific evidence and clinical practice. RESULTS: The diseases were divided into hypopigmented disorders, hyperpigmented disorders, scarring disorders, and alopecic disorders. Within each category, the etiology, clinical features, histopathology, and key histologic differential diagnoses are described and discussed. CONCLUSIONS: As many clinicians are taught that there are no effective treatment options or that these diseases are considered "cosmetic" in nature, patients often do not get a thorough medical workup or skin biopsy. This article aims to decrease the knowledge gap and serve as a resource for anyone involved in the care of patients with these cutaneous conditions.

Diagnostic utility of neural stem and progenitor cell markers nestin and SOX2 in distinguishing nodal melanocytic nevi from metastatic melanomas.

Sentinel lymph node evaluation is a critical component of melanoma staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. One of the well-known diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi, which has been demonstrated in up to 26% of lymphadenectomy specimens and specifically in melanoma patients. Melanocytic markers enhance the sensitivity of melanoma detection in sentinel lymph nodes. However, established markers such as anti-melan-A/MART1, S100 protein and SOX10 antibodies cannot discriminate melanoma metastasis from nodal nevi. Recent studies have demonstrated strong expression of neural stem/progenitor cell markers nestin and SOX2 in melanoma. In this study, we tested the diagnostic utility of nestin and SOX2 in differentiating metastatic melanomas from nodal nevi. Twenty-three lymph nodes with metastatic melanomas and 17 with nodal nevi were examined. Of the 23 metastatic melanomas, 18 showed diffuse and strong (3+) nestin, 4 showed rare cells with strong (3+) nestin, and one showed diffuse but faint (1+) nestin staining. Nuclear SOX2 was positive in 13 metastatic melanomas. In contrast, 15 nodal nevi showed no nestin, and 2 showed rare cells with very faint (<1+) nestin staining. SOX2 was negative in 13 nodal nevi. Overall, nestin was strongly expressed in metastatic melanomas (n=22/23; 96%), but not in nodal melanocytic nevi (n=15/17; 88%; P<0.0001). SOX2 was also expressed in metastatic melanomas (n=13/23; 57%) but not in the majority of nodal melanocytic nevi (n=13/16; 81%; P=0.02). In one lymph node harboring metastatic melan-A-negative desmoplastic melanoma, nestin and SOX2 strongly highlighted the infiltrating tumor cells, suggesting the potential clinical value of these two markers in desmoplastic melanoma lymph node biopsies. This study provides evidence that nestin and SOX2 can effectively differentiate nodal melanocytic nevi from metastatic melanomas and serve as powerful diagnostic adjuncts in melanoma staging.

Lipid synthesis and processing proteins ABHD5, PGRMC1 and squalene synthase can serve as novel immunohistochemical markers for sebaceous neoplasms and differentiate sebaceous carcinoma from sebaceoma and basal cell carcinoma with clear cell features.

BACKGROUND: Sebaceous carcinoma represents a rare and potentially fatal adnexal malignancy. Poorly-differentiated sebaceous carcinoma consisting of infiltrative basaloid tumor cells with inapparent lipid vesicles can mimic basal cell carcinoma (BCC). Conversely, other epithelial tumors can exhibit clear cell histopathology and mimic sebaceous carcinoma. At the present time, immunohistochemical markers unique for sebaceous carcinoma are limited. METHODS: We evaluated the expression of three lipid synthesis/processing protein markers alpha/beta hydrolase domain-containing protein 5 (ABHD5), progesterone receptor membrane component-1 (PGRMC1) and squalene synthase (SQS) in sebaceous carcinoma and investigated their utility in differentiating sebaceous tumors from BCC with clear cell features. Immunohistochemistry was performed on 23 sebaceous carcinomas, 14 sebaceomas and 14 BCCs with clear cell features. RESULTS: In sebaceous carcinomas, ABHD5 showed dispersed, cytoplasmic punctate and/or vesicular staining (n = 19/23, 83%), while PGRMC1 and SQS each showed vesicular and membranous staining in tumor cells (n = 22/23, 96%). In all sebaceomas, these markers highlighted tightly clustered lipid vesicles in sebocytes. All BCCs with clear cell features were negative for these three markers. CONCLUSION: ABHD5, PGRMC1 and SQS are novel markers for sebaceous carcinoma and can reliably distinguish sebaceous neoplasms from non-sebaceous tumors, specifically BCC with clear cell features.

Treatment options and emotional well-being in patients with rosacea: An unsupervised machine learning analysis of over 200,000 posts.

Background: Many patients with rosacea join online support groups to gather and disseminate information about disease management and provide emotional support for others. Objective: To better understand rosacea patient's primary concerns for the disease as well as their disease search patterns online. Methods: Overall, 207,038 posts by 41,400 users were collected from June 1, 2017, to June 1, 2022, in a popular online forum. We applied Latent Dirichlet Allocation (LDA), an unsupervised machine learning model, to organize the posts into topics. Keywords for each topic supplied by LDA were used to manually assign topic and category labels. Results: Twenty-three significant topics of conversation were identified and organized into 4 major categories, including Management (50.33%), Clinical Presentation (24.14%), Emotion (21.97%), and Information Appraisal (3.57%). Limitations: Although we analyzed the largest forum on the internet for rosacea, generalizability is limited given the presence of other smaller forums and the skewed demographics of forum users. Conclusion: Social media forums play an important role for disease discussion and emotional venting. Although rosacea management was the most frequently discussed topic, emotional posting was a significantly prevalent occurrence.

Primary Ewing's sarcoma of cranial bones: analysis of ten patients.

OBJECTIVE: Ewing's sarcomas are the second most common bone tumors in children and primary involvement of the cranium is uncommon. We analyzed retrospectively the data of ten patients with this rare subset of disease, who had been treated at our institute since 2005. Our aim was to assess the outcomes, recurrence rates and the selection of appropriate treatment methods. METHODS: The patients were reviewed with respect to their clinical presentations, treatment, and outcomes. Computed tomographic scanning of the brain was performed for all patients. Skeletal surveys with routine radiographs and technetium-99 bone scans to detect extracranial Ewing's sarcomas were performed for all patients. For all ten patients, radical tumor excision was achieved surgically. Chromosomal translocation studies were carried out on paraffin blocks for nine patients, using fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR). All patients were then subjected to adjuvant multidrug chemotherapy and radiotherapy. The follow-up periods ranged from 2 months to 5 years (mean, 17.6 months). RESULTS: The predominant presenting features were headaches, increased intracranial pressure, scalp swelling and trigeminal nerve involvement. The erosion of dura and intradural extension was noted in eight patients in our series. All nine patients, in whom FSIH and reverse transcriptase PCR (RT-PCR) was done, tested positive for EWS-FLI1(t22:12) translocation. All patients underwent radical excision within safe limits, followed by chemoradiation. Three patients had local recurrences, which were detected within 12 months after surgery. All three of them died within weeks of presentation with recurrence. One patient experienced a recurrence after 30 months. This recurrent tumor was completely excised, and additional chemotherapy was administered. There was a local recurrence again after 18 months that was treated with surgery and chemoradiation, and the patient is still surviving 5 years after the primary surgery. One patient had metastasis at presentation and died within 2 months of surgery. The remaining five seem to have good outcomes, though the follow-ups were not very long. CONCLUSION: The treatment of primary Ewing's sarcoma of the cranium still remains to be radical surgery, aggressive multidrug chemotherapy, and radiotherapy. Neoadjuvant chemotherapy may not work in patients with large intracranial extension due to raised pressure making decompression imperative. The outcome is usually good if there is no early recurrence. Early recurrence, presence of metastasis and extremes of age probably bears a poor outcome. However, a larger series is required to confirm these findings.

A Mutational Survey of Acral Nevi.

IMPORTANCE: Acral skin may develop nevi, but their mutational status and association with acral melanoma is unclear. OBJECTIVE: To perform targeted next-generation sequencing on a cohort of acral nevi to determine their mutational spectrum. DESIGN, SETTING, AND PARTICIPANTS: Acral nevi specimens (n = 50) that had been obtained for diagnostic purposes were identified from the pathology archives of a tertiary care academic cancer center and a university dermatology clinic. Next-generation sequencing was performed on DNA extracted from the specimens, and mutations called. A subset of samples was stained immunohistochemically for the BRAF V600E mutation. RESULTS: A total of 50 nevi from 49 patients (19 males and 30 females; median [range] age, 48 [13-85] years) were examined. Analysis of the sequencing data revealed a high prevalence of BRAF mutations (n = 43), with a lower frequency of NRAS mutations (n = 5). Mutations in BRAF and NRAS were mutually exclusive. CONCLUSIONS AND RELEVANCE: In this cohort study, nevi arising on mostly sun-protected acral skin showed a rate of BRAF mutation similar to that of acquired nevi on sun-exposed skin but far higher than that of acral melanoma. These findings are in contrast to the well-characterized mutational landscape of acral melanoma.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1ß in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Gnathodiaphyseal dysplasia: Severe atypical presentation with novel heterozygous mutation of the anoctamin gene (ANO5).

Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~2months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.