Immunohistochemical Staining Patterns Research Articles

Epithelioid Trophoblastic Tumor Predominant Mixed Germ Cell Tumor of the Testis: A Case Report and Review of the Literature.

An epithelioid trophoblastic tumor is a rare form of gestational trophoblastic neoplasia that mostly affects the uterus and endocervix in female patients of the reproductive age group. The tumor is believed to arise from chorion leave-type intermediate trophoblast. The epithelioid trophoblastic tumor in men is extremely rare and mostly described in association with mixed germ cell tumors of the testis. It is more commonly identified at the metastatic sites than in the testis. The epithelioid trophoblastic tumor should be differentiated from placental site trophoblastic tumor and squamous cell carcinoma. The distinctive morphology and characteristic immunohistochemical staining pattern help differentiate epithelioid trophoblastic tumors from other neoplasms. Only 7 male patients with epithelioid trophoblastic tumors have been described to date. Of these 7 patients, 4 were in metastatic sites, 2 in the testis, and 1 in the lung without the involvement of the testis or retroperitoneum. The proportion of epithelioid trophoblastic tumors was only 5% in the 2 patients with testis involvement. Here, we report the third patient with a primary testicular epithelioid trophoblastic tumor in a young man. Further, this is the first report to document epithelioid trophoblastic tumor as dominant histology in a testicular germ cell tumor.

P53 Immunohistochemistry staining patterns and prognosis significance in 212 cases of non-endometrioid endometrial cancer

ObjectiveTo investigate the immunohistochemistry (IHC) staining pattern and prognostic significance of p53 in non-endometrioid endometrial cancer (non-EEC). MethodsThis study retrospectively included 212 non-EEC patients, with histological types including serous carcinoma (SC), clear cell carcinoma (CCC), mixed carcinoma (MC), undifferentiated carcinoma (UC), and carcinosarcoma (CS). p53 IHC was interpreted as normal/wild-type and abnormal/mutant-type, the latter including overexpression, complete absence, and cytoplasmic staining patterns. Moreover, uncommon p53 subclonal/heterogeneous staining patterns were described. Disease-free survival (DFS) and overall survival (OS) were employed as endpoints to evaluate the prognostic significance of p53. ResultsIn 212 non-EEC cases, 50 (23.6 %) were p53 wild-type, while 162 (76.4 %) displayed abnormal p53 staining. Overexpression was the predominant abnormal p53 staining pattern (122/162), complete absence followed (33/162). All SCs exhibited the mutant p53 staining pattern. The p53 abnormal expression rates in CCC, MC, UC, and CS were 37.5 %, 78.9 %, 35.7 %, and 75.7 %, respectively. Interestingly, of the 12 MC cases with SC components, barring one with p53 subclonal staining, all showed the mutant-type staining. The concordance rate for p53 expression between epithelial and mesenchymal components of CS was 94.3 % (66/70). Kaplan-Meier curves indicated patients with p53 abnormalities had worse DFS compared to those with wild-type p53 (P=0.025). Multivariate Cox regression confirmed that p53 (HR: 2.270, 95 % CI: 1.124–4.586, P=0.022) independently predicted DFS in non-EEC patients, though not for OS. ConclusionsNon-EEC patients with various histological types exhibit different p53 staining patterns. However, abnormal p53 expression, regardless of histological type, implies a poor DFS in non-EEC patients.

The role of progesterone and estrogen receptors in treatment choice after endometriosis surgery: A cross-sectional study.

The lack of improvement in some endometriotic people's pain after surgery even while using hormone treatment may suggest an inappropriate response to routine hormonal therapies. This study aimed to determine a cut-off point for selecting the most appropriate treatment based on the hormone receptors of endometriotic lesions. In this cross-sectional study, by reviewing the medical records of participants and testing their archive samples and phone interviews (if needed), 86 symptomatic women after endometriosis surgery who were operated into governmental hospitals, Shahid Faghihi and Hazrate Zeinab Shiraz Iran were enrolled between March 2017 and March 2019. Women were divided into 2 groups: responsiveness (n = 73 for dysmenorrhea, n = 60 for dyspareunia) to medical treatment and surgery, and unresponsiveness (n = 13, n = 7). We examined the pathological slides of 86 women to determine the amount of hormone receptors and the relationship between the type of medical treatment and the level of hormone receptors on pain relief within 1 yr after surgery. Based on the receiver operating characteristic curve, dysmenorrhea in the presence of tissue estrogen receptors 60% (p = 0.1065), and dyspareunia in the presence of tissue progesterone receptors 80% (p = 0.0001) responded well to medical treatment after surgery. In the presence of endometrioma-dysmenorrhea showed the best response to oral contraceptive pills (69.4%), while in deep infiltrative endometriosis-dyspareunia showed the best response to progesterone treatment (75%). Prescribing an appropriate hormone therapy based on a specific immunohistochemistry staining pattern can improve the life quality of postoperative endometriosis individuals.

P53 Abnormal Oral Epithelial Dysplasias are Associated With High Risks of Progression and Local Recurrence—A Retrospective Study in a Longitudinal Cohort

Grading of oral epithelial dysplasia (OED) can be challenging with considerable intraobserver and interobserver variability. Abnormal immunohistochemical (IHC) staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with a diagnosis of reactive, nondysplastic lesions, low-grade lesions (mild OED and moderate OED) and high-grade lesions (HGLs; severe OED/carcinoma in situ). Tissue microarrays were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 IHC, and p16 IHC. The staining results were reviewed by 2 pathologists blinded to clinical outcome. Samples were categorized into p53 abnormal OED (n = 46), p53 conventional OED (n = 118), and p53 human papillomavirus (HPV) OED (HPV associated) (n = 12) using a previously published pattern-based approach. All cases of p53 HPV OED (HPV associated) were identified in HGLs. In contrast, cases of p53 abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED/carcinoma in situ (51%). None of the 27 reactive or nondysplastic lesions showed abnormal p53 staining patterns. Among the 135 low-grade lesions, 23 cases (17.0%; 2 mild OEDs and 21 moderate OEDs) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster progressors showed abnormal p53 patterns. Survival analysis revealed that p53 abnormal OED had significantly poorer progression-free probability (P < .0001) with hazard ratio of 11.24 (95% CI, 4.26-29.66) compared with p53 conventional OED. Furthermore, p53 abnormal OED had poorer local recurrence–free survival compared with p53 wild-type OED (P = .03). The study supports that OED with p53 abnormal pattern is at high risk for progression and recurrence independent of the dysplasia grade.

Correlation between immunohistochemical staining and clinicopathological findings in endometrial carcinoma.

To analyze the immunohistochemical staining pattern of mismatch repair (MMR) proteins and p53 in endometrial carcinoma cases, including different subtypes and stages, to gain insights into their role in the pathogenesis and clinical behaviour of this malignancy. In this study, we investigate the association between MMR deficiency, p53 mutational status, and clinical outcomes in various subtypes of endometrial carcinoma. The immunohistochemical staining pattern of MMR proteins in 96 cases of endometrial carcinoma have been analyzed, including 72 endometrioid, 14 papillary serous, 5 clear cell, and 5 mixed Müllerian tumor. The results showed that 36 cases were MMR deficient, with the majority being of endometrioid subtype. The p53 immunostain showed a mutational pattern in a subset of cases, with a documented dismal prognosis. However, aforementioned stains failed to predict synchronous or metachronous cancers in 5 patients. These findings highlight the importance of MMR and p53 immunohistochemical staining in the classification, and prognosis of endometrial carcinoma.

Immunohistochemical staining patterns of non-functioning pituitary adenomas and presentation of secondary hormonal deficiencies

Immunohistochemical staining patterns of non-functioning pituitary adenomas and presentation of secondary hormonal deficiencies

Integration of Pathological Criteria and Immunohistochemical Evaluation for Invasive Lobular Carcinoma Diagnosis: Recommendations From the European Lobular Breast Cancer Consortium

Invasive lobular carcinoma (ILC) is the second most frequent type of breast cancer (BC) and its peculiar morphology is mainly driven by inactivation of CDH1, the gene coding for E-cadherin cell adhesion protein. ILC-specific therapeutic and disease-monitoring approaches are gaining momentum in the clinic, increasing the importance of accurate ILC diagnosis. Several essential and desirable morphologic diagnostic criteria are currently defined by the World Health Organization, the routine use of immunohistochemistry (IHC) for E-cadherin is not recommended. Disagreement in the diagnosis of ILC has been repeatedly reported, but interpathologist agreement increases with the use of E-cadherin IHC. In this study, we aimed to harmonize the pathological diagnosis of ILC by comparing 5 commonly used E-cadherin antibody clones (NCH-38, EP700Y, Clone 36, NCL-L-E-cad [Clone 36B5], and ECH-6). We determined their biochemical specificity for the E-cadherin protein and IHC staining performance according to type and location of mutation on the CDH1 gene. Western blot analysis on mouse cell lines with conditional E-cadherin expression revealed a reduced specificity of EP700Y and NCL-L-E-cad for E-cadherin, with cross-reactivity of Clone 36 to P-cadherin. The use of IHC improved interpathologist agreement for ILC, lobular carcinoma in situ, and atypical lobular hyperplasia. The E-cadherin IHC staining pattern was associated with variant allele frequency and likelihood of nonsense-mediated RNA decay but not with the type or position of CDH1 mutations. Based on these results, we recommend the indication for E-cadherin staining, choice of antibodies, and their interpretation to standardize ILC diagnosis in current pathology practice.

Immunohistochemical findings and clinicopathological features of breast cancers with pathogenic germline mutations in Non-BRCA genes

Deleterious germline mutations in multiple genes confer an increased breast cancer (BC) risk. Immunohistochemical (IHC) expression of protein products of mutated high-risk genes has not been investigated in BC. We hypothesized that pathogenic mutations may lead to an abnormal IHC expression pattern in the tumor cells. BCs with deleterious germline mutations in CHEK2, ATM, PALB2 &PTEN were identified. Immunohistochemistry was performed using Dako staining platform on formalin fixed paraffin embedded tumor tissue. Primary antibodies for PALB2 (ab202970), ATM [2C1(1A10)}, CHK2 (EPR4325), and PTEN (138G6) proteins were used for BCs with respective deleterious mutations. IHC expression was assessed in tumor and adjacent benign breast tissue. Total 27 BCs with 10 CHEK2, 9 ATM, 6 PALB2 & 2 PTEN deleterious germline mutations were identified. IHC staining was performed on 8 CHEK2, 7 ATM, 6 PALB2 & 2 PTEN cases. Abnormal CHEK2 IHC staining was identified in 7/8(88%) BCs. Three distinct CHK2 IHC patterns were noted: 1) Strong diffuse nuclear positivity (5 BC), 2) Null-pattern (2 BC), & 3) Normal breast–like staining in 1 BC Four of 5 (80%) strong CHK2 staining BC had missense CHEK2 mutations. Null-pattern was present with a missense & a frameshift mutation. Normal breast-like CHEK2 IHC staining pattern was present in 1 BC with CHEK2 frameshift mutation. Loss of nuclear/cytoplasmic PTEN IHC expression was noted in 2 in-situ carcinomas. Abnormal PTEN and CHK2 IHC were present in atypical ductal hyperplasia and flat epithelial atypia. ATM and PALB2 IHC expression patterns were similar in tumor cells and benign breast epithelium: mild to moderate intensity nuclear and cytoplasmic staining. We report abnormal CHEK2 IHC expression in 88% of BCs with pathogenic CHEK2 mutations. With PTEN and CHEK2 pathogenic mutations, abnormal IHC patterns are seen in early atypical proliferative lesions. IHC may be applied to identify CHEK2 &PTEN mutated BCs and precursor lesions.

TP53 mutations and the association with platinum resistance in high grade serous ovarian carcinoma

ObjectivesAlterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance. MethodsNext generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed. Results209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance. ConclusionsTP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation.

Abstract 5094: Immunotherapy in advanced cutaneous non-melanomatous spindle cell neoplasms

Abstract Background: Non-melanomatous cutaneous spindle cell neoplasms (NMCSpC) are a rare group of malignancies including pleomorphic dermal sarcoma (PDS) and spindle-cell cutaneous squamous cell carcinoma (SpSCC). They present a diagnostic challenge with overlapping morphological features and variable patterns of immunohistochemical (IHC) staining. There is a lack of consensus on how to best manage advanced NMCSpC and limited reports of immunotherapy (IO) responses. This study reviews the efficacy of IO in NMCSpC and performs comprehensive tumor profiling to identify biological rationale for IO use in this rare group of tumors. Methods: We performed a single-center retrospective review of all locally-advanced or metastatic NMCSpCs treated with IO. Blinded histopathology reviews occurred to confirm each diagnosis. Overall response rates (ORR) were collected as per Response Evaluation Criteria in Solid Tumors 1.1 or Positron Emission Tomography Response Criteria 1.0. Comprehensive tumor profiling included whole exome sequencing for tumor mutational burden (TMB) and ultraviolet(UV)-signatures, and IHC for immune-cell infiltration (CD103/CD4/CD3/CD8/CD20) and immune-checkpoint expression (PD-L1/TIGIT/LAG3). Results: 7 patients were identified. Median follow up was 18.1 months (range: 5.3-34.7). ORR 86% (6/7) with five complete responses (CR). One patient who achieved stable disease progressed. Responses were durable with two patients in CR &amp;gt;30 months after IO commencement. Blinded pathological review identified 3 SpSCC, 2 PDS and 2 spindle cell tumors of unclear sub-classification. All patients had high TMB and UV-signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression (Table 1). Conclusion: In advanced NMCSpC, excellent responses to IO with durable disease control was observed. IO is worthy of further exploration in these patients. UV-signatures and high TMB could be used to help select patients for treatment. Immunohistochemistry (IHC)^, tumor mutational burden and ultraviolet signatures Patient T-cell markers B-cell marker Immune-checkpoints Tumor mutational burden (mutations/megabase) Ultraviolet-mutational signature Best response assessment# CD103 CD4 CD3 CD8 CD20 PD-L1 TIGIT LAG3 1 1 20 1 1 0 7 0 0 17.94 Yes Stable metabolic response 2 1 20 30 10 0 100 0 10 35.34 Yes Complete metabolic response 3 1 10 10 5 0 5 0 0 104.87 Yes Complete metabolic response 4 1 0 1 0 0 0 0 0 74.04 Yes Partial metabolic response 5* NA NA NA NA NA NA NA NA 29 Yes Complete metabolic response 6 1 0 0 5 0 0 0 4 12.02 Yes Complete metabolic response 7 1 0 5 1 0 0 0 0 41.17 Yes Complete response ^IHC scores are % of positively stained cells, except for PD-L1 which is combined positive score (CPS). *Insufficient tissue for IHC on Patient 5. #As per PERCIST 1.0 on FDG-PET/CT or RECIST1.1 on CT. Citation Format: Luke S. McLean, Annette M. Lim, Christopher Angel, Richard J. Young, Angela Pizzolla, Stuart Archer, Alesha A. Thai, Benjamin Solomon, Jeremy Lewin, Danny Rischin. Immunotherapy in advanced cutaneous non-melanomatous spindle cell neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5094.

Recurrent MTOR Mutations in Renal Cell Carcinoma With Fibromyomatous Stroma: A Report of 2 Tumors.

Renal cell carcinoma with fibromyomatous stroma, recognized as a provisional entity in the current 2022 World Health Organization classification of renal neoplasms, is rare. Recent evidence suggests recurrent alterations in the mTOR pathway, supporting its recognition as a distinct entity. Herein, we report 2 renal cell carcinomas with fibromyomatous stroma with MTOR mutations occurring in 62- and 72-year-old women and review the literature to support its recognition as a distinct entity, focusing on the characteristic morphology, immunohistochemical staining patterns as well as genetic alterations.

Ever Expanding Morphologic Patterns of Mesonephric-like Adenocarcinomas of the Uterine Corpus: A Report of Two Tumors and a Brief Review of the Literature.

Mesonephric-like adenocarcinoma (MLA) of the endometrium shows a variety of morphologic appearances, including small glands, tubules with eosinophilic materials in the lumen, prominent papillary patterns, spindled cells, solid formations, and corded and hyalinized patterns. Unique morphology, characteristic immunohistochemical staining patterns, molecular alterations, and awareness of the pathologists make it possible to identify this tumor accurately. This report of two additional morphologic patterns, intestinal goblet cells mimicking intestinal-type mucinous carcinoma and squamous differentiation with spindle and epithelioid cells mimicking carcinosarcoma of the endometrium will expand the literature on MLA.

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Endometrial Cancer: A Review on Immunohistochemistry Staining Patterns and Clinical Implications.

Among the four endometrial cancer (EC) TCGA molecular groups, the MSI/hypermutated group represents an important percentage of tumors (30%), including different histotypes, and generally confers an intermediate prognosis for affected women, also providing new immunotherapeutic strategies. Immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6 and PMS2) has become the optimal diagnostic MSI surrogate worldwide. This review aims to provide state-of-the-art knowledge on MMR deficiency/MSI in EC and to clarify the pathological assessment, interpretation pitfalls and reporting of MMR status.

Incidence and Risk Factors for Recurrence and Progression of HPV-Independent Vulvar Intraepithelial Neoplasia.

Human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. Patients with HPV-independent VIN between 1991 and 2019 in a selected region were identified from the Dutch Nationwide Pathology Databank (Palga). Data were collected from the pathology reports. Crude and European age-standardized incidence rates were calculated for 10-year periods. Kaplan-Meier analyses were performed to determine the cumulative recurrence and cancer incidence, followed by Cox regression analyses to identify associated risk factors. A total of 114 patients were diagnosed with solitary HPV-independent VIN without prior or concurrent vulvar cancer. The European age-standardized incidence rate increased from 0.09 to 0.69 per 100,000 women-years between 1991-2010 and 2011-2019. A cumulative recurrence and cancer incidence of 29% and 46% were found after 8 and 13 years of follow-up, respectively. Nonradical surgery was identified as the only independent risk factor for recurrent HPV-independent VIN. Risk factors associated with progression to cancer were increasing age and a mutant p53 immunohistochemical staining pattern. The incidence of detected HPV-independent VIN has substantially increased the last decade and the subsequent recurrence and vulvar cancer risks are high. Although HPV-independent VIN may present as a wide morphologic spectrum, surgical treatment should aim for negative resection margins followed by close surveillance, especially for p53 mutant lesions.

Ovarian carcinosarcomas: p53 status defines two distinct patterns of oncogenesis and outcomes.

Ovarian carcinosarcoma (OCS) is a rare and lethal type of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, we aim to evaluate the molecular features of OCS and elucidate their clinical significance. We examined 30 OCS by immunohistochemistry (IHC) and targeted panel sequencing collected from a single institution (2003-2013) as the initial molecularly characterized cohort (Cohort A). From November 2016 to April 2023, we collected an additional 67 OCS cases from three institutions across British Columbia and Alberta as the contemporary cohort (Cohort B) for clinical correlation. The Kaplan-Meier method was used to estimate overall and progression-free survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant. The majority of OCS (82%) in the initial Cohort A were p53-mutated, and the carcinomatous component displayed the histological and molecular features of a high-grade tubo-ovarian serous carcinoma (HGSC-like). In a minority of OCS, the epithelial components were characteristics of endometrioid or clear cell carcinomas, and IHC staining was wild type for p53. In the contemporary Cohort B, we observed the same histological findings related to the p53 IHC staining pattern. The median overall survival of the p53-mutated HGSC-like OCS (47 patients) was significantly higher (43.5 months) compared with that of the p53 wild-type OCS (10 patients, 8.8 months; P < 0.01). Pathogenic BRCA1/2 germline/somatic mutations were observed in 7 patients (17.5%) of HGSC-like OCS, and all these patients were alive at 3 years from diagnosis compared to a 51% 3-year survival among the patients with BRCA1/2 wild-type HGSC-like OCS (33 patients) (p = 0.022). Majority of patients (6/7) with BRCA1/2-mutated OCS received poly (ADP-ribose) polymerase inhibitor as maintenance therapy in this cohort. Most OCSs have a morphologic and molecular profile resembling HGSC; however, some OCSs display a molecular profile that suggests origin through non-serous oncogenic pathways. This molecular distinction has both prognostic and treatment (predictive) implications. These findings underscore the importance of routine p53 IHC testing on all OCS and BRCA1/2 testing on p53-mutated OCS.

PD-L1 and PD-1 Expression in Early Stage Uterine Endometrioid Carcinoma.

Immune checkpoint inhibitors (ICI) and tumor-infiltrating lymphocytes (TILs) for cancer treatment in clinical oncology have revolutionized patient care. However, no gold standard exists for the criteria of analytical validity of TILs of different types of cancer. Clinicopathological data from 60 patients with endometrioid carcinoma (EC) who had undergone surgical treatment at the Gyeongsang National University Hospital between January 2002 and December 2009, were investigated. The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PDL1) expression levels were characterized by immunohistochemical staining patterns, and the interpretations derived from machine learning morphometric analysis (Genie) and the pathologists' assessments were compared. In solid tumors, pathologists assessed the proportion of positive cells in each core of the tissue microarray. For Genie, the proportion of positive cells in the entire core and the number of positive cells per 1 mm2 were used. Both the pathologists and Genie identified the same trend in association with tumor size, with significant differences (p=0.026, p=0.033). Genie expression showed a significant association with PD1 expression, and pathologists identified a significant association with PDL1 expression in immune cells. The PD1 expression levels identified in immune cells of EC specimens were similar between the pathologists and Genie, suggesting that there is little resistance to the introduction of morphometric analysis. To our knowledge, this is the first study to introduce and validate machine learning as an integrated method for predicting prognosis and treatment based on PD1 expression in EC tumor microenvironments.

Claudin-4 Upregulation in Acantholytic and Autoimmune-Mediated Bullous Disorders.

Claudin-4 is a key component of tight junctions, which play an important role in the formation of the epidermal barrier by forming a circumferential network in the granular layer that serves as a gatekeeper of the paracellular pathway. The aim of this study is to illustrate claudin-4 immunohistochemical staining patterns of different blistering disorders. We collected 35 cases, including two Hailey-Hailey disease, one Darier disease, three Grover disease, one acantholytic acanthoma, two warty dyskeratoma, 11 pemphigus vulgaris (PV) including six mucosal PV, and two pemphigus foliaceus. For comparison, we included five cases of normal skin, five eczema, and three bullous pemphigoid cases. Claudin-4 demonstrated weak-to-moderate expression in keratinocytes located in the stratum granulosum, keratinocytes surrounding hair follicles, and adnexal glands. Further, claudin-4 exhibited moderate-to-strong membranous staining in disrupted keratinocytes surrounding and within the acantholytic and bullous areas in 16/22 of the acantholytic cases (not seen in the six cases of mucosal PV) and all three bullous pemphigoids. This finding suggests that claudin-4 is upregulated in these conditions, which may be a compensatory response to the disrupted barrier function. This finding could shed light on the molecular mechanisms underlying disrupted barrier function in blistering disorders, independent of the specific underlying disease mechanism.

ACTB::GLI1 Gene Fusion Small Bowel Mesenteric Tumor; a Case Report and Review of the Literature

Abstract Introduction/Objective GLI1 encodes a transcription factor that targets cell cycle regulators affecting stem cell proliferation. Activation of the GLI (glioma-associated oncogene homologue 1). GLI activity in adult tissues is restricted but has been identified in various neoplasms, as a result of mutations in the PTCH (patched) or SMOH (smoothened) genes, encoding components of the sonic hedgehog pathway, or by amplification of GLI. The B-actin (ACTB) gene, encoding an essential cytoskeletal component, is under the control of a conserved, strong, and complex promoter that assures a high level of expression in non-muscle cells. ACTB::GLI1 gene fusions have been reported in the tongue as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular tumors with t (7;12) translocation. Methods/Case Report We report a case of 53-year-old male presented to the hospital with dizziness and bloody stools. CT scan of the abdomen and pelvis revealed a 10.5 x 7.7 cm large complex cystic and solid mass of the right lower quadrant of the abdomen adjacent to the cecum and terminal ileum. The patient has a past medical history of testicular germ cell tumor and underwent orchiectomy with adjuvant chemotherapy 30 years ago. The mass was excised and histological examination of the mass showed an unencapsulated, relatively circumscribed neoplasm composed of sheets of monomorphic bland spindle to ovoid cells. Immunohistochemical (IHC) stains, including pan- CK, SALL4, c-Kit, CD34, SMA, MDM2, HMB45, and MART1, were all negative. NGS sarcoma fusion panel was done and revealed ACTB::GLI1 gene fusion. The tumor was finally diagnosed as GLI1 -rearranged enteric tumor. Results (if a Case Study enter NA) NA Conclusion our case, in addition to, previously reported cases in the literature support the existence of a newly identified, seemingly discrete group of soft tissue tumors at different body locations. The morphology of these tumors is somewhat variable, making identifying and diagnosing these tumors more challenging. In addition to the morphologic variance, the diagnosis of these tumors in unusual locations is not uncommon, with some variations in IHC staining patterns. Identifying the molecular pattern of these tumors and the biological mechanism will facilitate more effective treatment options for patients, including targeted therapy.

Case Report: Identification of a novel STAT3 mutation in EBV-positive inflammatory follicular dendritic cell sarcoma

EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is an uncommon disease primarily observed in Asia. It is characterized by the development of tumors believed to originate from follicular dendritic cells (FDC). The consistent association between this condition and clonal EBV infection suggests EBV’s involvement as an etiological factor. However, diagnosing EBV+ IFDCS can be challenging due to its morphological variability and diverse immunohistochemical staining patterns. The genetic characteristics of EBV+ IFDCS remain insufficiently understood. To address this knowledge gap, we present a case study of a 47-year-old male patient diagnosed with EBV+ IFDCS. We utilized a Next-generation sequencing (NGS) platform to investigate the genetic profile of the tumor cells. We identified a single pathogenic mutation (G618R) in the STAT3 gene. This finding provides valuable insights into the genetic alterations associated with EBV+ IFDCS and potentially contributes to our understanding of the disease’s pathogenesis.

THU525 Atypical Presentation Of Parathyroid Carcinoma In The Lungs

Abstract Disclosure: J.N. Jacinto: None. O. Reyes: None. M. Cating-Cabral: None. R. Santiago: None. J. Andal: None. A 66-year-old female with a history of parathyroid adenoma underwent partial parathyroidectomy and thyroidectomy of the right lobe in 2006. She has the following comorbidities: pre-diabetes, hypertension, multiple liver cysts, medullary nephrocalcinosis and nephrolithiasis, ureterolithiasis and uterine intramural myoma. She also has a strong familial disposition of endocrine tumors. During the last quarter of 2018, parathyroid hormone and calcium levels were elevated and parathyroid imaging revealed an adenoma on the posteromedial aspect of the left thyroid lobe. Removal of the adenoma was offered but insisted on medical treatment. In 2022, she was admitted for subarachnoid hemorrhage due to fall. There was an incidental finding of a lung mass with minimal pleural effusion on the right lung lobe. PET-scan revealed five FDG-avid nodules (SUV up to 9.6) with the largest in the right middle lobe measuring 2 x 2 x 2 cm. Percutaneous needle biopsy was performed which showed a tumor with fairly uniform cells in organoid nests and solid clusters. By immunohistochemistry (IHC), the tumor cells were diffusely and strongly positive for CK and GATA-3; focally positive for chromogranin and synaptophysin; and negative for TTF-1, Pax-8, and S100. This was signed out as an epithelial tumor with neuroendocrine features; the differential diagnosis includes pulmonary neuroendocrine tumor versus metastasis from the prior parathyroid lesion. She subsequently underwent completion thyroidectomy and video-assisted thoracoscopic surgery. The lung wedge resections both showed tumors with similar morphology and IHC staining pattern as the biopsy. Additional stains were also performed to rule out other entities, which were all negative (CK7, CK20, CD56, mammaglobin, GCDFP-15, TTF-1, S100, ER, Pax-8, HSA, and SALL-4). The Ki-67 proliferation index was 17.26%. Because the overall findings were not definitive, comprehensive genomic profiling by next generation sequencing (NGS) was recommended and subsequently performed. NGS showed gene alteration in CDC73, with a variant allele frequency of 50%; this finding has been documented in parathyroid carcinoma. Pre-operative parathyroid hormone levels remained unchanged (408 to 397 pg/ml) despite surgery. Currently, there is no available targeted therapy to address her genomic alteration. Hyperparathyroidism-jaw tumor syndrome was entertained. The multidisciplinary team advised en-bloc resection of the lung tumor and additional gene testing for family members. She opted for palliative care and is on cinacalcet for her hyperparathyroidism. Presentation: Thursday, June 15, 2023