KEAP1-NRF2 pathway as a novel therapeutic target for EGFR-mutant non-small cell lung cancer.

BACKGROUND: Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid-2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy, however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. METHODS: We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. RESULTS: Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Co-treatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. CONCLUSION: We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in TKI-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-tyrosine kinase inhibitors.

Management strategy of primary ovarian mucinous carcinoid tumor: A rare case report.

RATIONALE: Primary ovarian carcinoid tumors are rare neoplasms, first reported in 1939, with approximately 30 cases reported thus far. It is categorized into insular, trabecular, strumal, and mucinous types. Mucinous forms are extremely rare, comprising < 2% of all primary ovarian carcinoid tumors. PATIENT CONCERNS: A 40-year-old gravida 3, para 0 woman visited our clinic with a 3-month history of lower abdominal pain. Ultrasound and abdominal pelvic computed tomography revealed a large, poorly enhancing soft tissue mass in the right adnexa (about 9.4 × 7.0 × 6.8 cm sized). Laparoscopic surgery was performed to a definitive diagnosis, including right salpingo-oophorectomy, left ovarian biopsy, and ascites washing cytology. DIAGNOSIS: The patient was diagnosed with primary ovarian mucinous carcinoid tumor and received related treatment. OUTCOMES: After treatment, the patient symptoms improved, and he was discharged. LESSONS: Approximately 40% of primary ovarian carcinoid tumors with insular morphology present in pure form, and mucinous forms are extremely rare. At present, the main diagnostic methods in cases of primary ovarian mucinous carcinoid tumor include macroscopic examination, histopathology and imaging examination. The main treatment modalities for primary ovarian mucinous carcinoid tumor are surgery. postoperative chemotherapy remains controversial.

Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Prognostic Impact of Reactive Oxygen Species Modulator 1 in Surgically Resected Epidermal Growth Factor Receptor-Mutant Lung Adenocarcinomas.

INTRODUCTION: Reactive oxygen species modulator 1 (Romo1) is a novel protein that is critically involved in the intracellular production of reactive oxygen species. Evidence has revealed that Romo1 is associated with treatment outcomes of various human malignancies, including lung cancer. However, the clinical implications of this protein in surgically resected lung cancers harboring epidermal growth factor receptor (EGFR) mutations have not been investigated. METHODS: Data were collected from patients who underwent curative resection of EGFR-mutant lung adenocarcinoma. Romo1 protein expression levels were measured in the tumor tissue using immunohistochemical staining and evaluated semi-quantitatively using the histochemical score. Univariate and multivariate analyses were performed to identify the clinicopathological parameters that may be associated with clinical outcomes. RESULTS: A total of 98 samples were analyzed. Using the cutoff H score of 200, the population was classified into low (n = 73) and high (n = 25) Romo1 groups. Romo1 expression was significantly higher in smokers, patients with stage III disease, and patients who experienced recurrence after surgery (all p < 0.05). Multivariate analyses showed that advanced-stage and poorly differentiated cancers were associated with shorter disease-free survival (DFS). In addition, high Romo1 expression was independently associated with poor DFS (hazard ratio = 2.18, 95% confidence interval: 1.10-4.32, p = 0.0261). CONCLUSIONS: Our data showed that Romo1 overexpression was significantly associated with early recurrence in patients with resected EGFR-mutant lung adenocarcinoma. Although large-scale studies are required, Romo1 may play a prognostic role in this patient population.

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

BACKGROUND/AIM: Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. MATERIALS AND METHODS: Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. RESULTS: The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. CONCLUSION: MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

Cytological Features of Fibrin-associated Diffuse Large B-cell Lymphoma Arising in Retroperitoneal Pseudocyst: The First Case Report.

BACKGROUND/AIM: Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is frequently associated with the Epstein-Barr virus (EBV) and manifests as non-mass-forming microscopic lesions within fibrin-rich lesions. Herein, we describe the cytological features of FA-DLBCL. CASE REPORT: A 72-year-old man presented with a large retroperitoneal cystic mass that was treated by cyst aspiration and laparoscopic excision. Individually dispersed large, atypical cells in a necrotic background contained scant cytoplasm and hyperchromatic nuclei with irregular nuclear contours, frequent karyorrhectic debris, and mitotic figures. A fibrinous exudate with necrotic material attached to the inner surface of the cystic mass contained large, atypical cells that were individually scattered or arranged in small clusters. These were positive for cluster of differentiation 20 and Epstein-Barr virus-encoded RNA in situ hybridization. CONCLUSION: We cytologically characterized FA-DLBCL as large, atypical cells that were individually scattered or arranged in small clusters in a necrotic background. To the best of our knowledge, we revealed the cytological features of FA-DLBCL.

Prediction of homologous recombination deficiency from Oncomine Comprehensive Assay Plus correlating with SOPHiA DDM HRD Solution.

OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors are used for targeted therapy for ovarian cancer with homologous recombination deficiency (HRD). In this study, we aimed to develop a homologous recombination deficiency prediction model to predict the genomic integrity (GI) index of the SOPHiA DDM HRD Solution from the Oncomine Comprehensive Assay (OCA) Plus. We also tried to a find cut-off value of the genomic instability metric (GIM) of the OCA Plus that correlates with the GI index of the SOPHiA DDM HRD Solution. METHODS: We included 87 cases with high-grade ovarian serous carcinoma from five tertiary referral hospitals in Republic of Korea. We developed an HRD prediction model to predict the GI index of the SOPHiA DDM HRD Solution. As predictor variables in the model, we used the HRD score, which included percent loss of heterozygosity (%LOH), percent telomeric allelic imbalance (%TAI), percent large-scale state transitions (%LST), and the genomic instability metric (GIM). To build the model, we employed a penalized logistic regression technique. RESULTS: The final model equation is -21.77 + 0.200 × GIM + 0.102 × %LOH + 0.037 × %TAI + 0.261 × %LST. To improve the performance of the prediction model, we added a borderline result category to the GI results. The accuracy of our HRD status prediction model was 0.958 for the test set. The accuracy of HRD status using GIM with a cut-off value of 16 was 0.911. CONCLUSION: The Oncomine Comprehensive Assay Plus provides a reliable biomarker for homologous recombination deficiency.

Next Generation Sequencing Analysis of Fibrin-associated Large B-cell Lymphoma Reveals Pathogenic Single Nucleotide Variants.

BACKGROUND/AIM: Fibrin-associated large B-cell lymphoma (FA-LBCL) is a newly identified subtype of Epstein-Barr virus (EBV)-associated lymphoma. Arising within fibrinous material in confined spaces, FA-LBCL is associated with chronic inflammation. We herein report histopathologic features and molecular alterations of three cases of FA-LBCL to refine this new disease entity. MATERIALS AND METHODS: We performed immunohistochemical staining for CD3, CD20, CD10, Bcl-2, Bcl-6, MUM-1, CD10, and c-Myc and in situ hybridization for EBV-encoded RNA. Additionally, targeted DNA sequencing was conducted using commercially available gene panels. RESULTS: Three cases of FA-LBCL developed underlying lesions of retroperitoneal cyst, cardiac myxoma, and pancreatic cyst. Histopathologic features of these lesions were characterized by aggregates of atypical large cells in a background of fibrinous cellular debris. Atypical lymphoid cells were positive for CD20, Bcl-2, MUM-1, and EBV-in situ hybridization, negative for CD10, and variably positive for Bcl-6 and c-Myc. NGS analysis revealed the presence of pathogenic mutations in BRIP1, SOCS1, and KRAS. CONCLUSION: This is the first report of NGS analysis in FA-LBCL cases. It provides precise clinicopathological and molecular traits and allows its recognition as a new entity.

Coexistence of Colorectal Cancer and Immunoglobulin G4-Related Disease in the Same Lesion: A Rare Case with Molecular Classification.

Immunoglobulin G4-related disease (IgG4-RD) is a novel fibroinflammatory disorder characterized by enlargement of the involved organs, elevated IgG4 levels, and abundant infiltration of IgG4-positive plasma cells. Indeed, primary colon cancers arising from IgG4-RD are rare. This case report describes a rare occurrence of simultaneous colorectal cancer and IgG4-RD in the same lesion in a 62-year-old male patient. The patient underwent a right hemicolectomy under the suspicion of primary colon cancer. The mass was grossly well-defined and yellowish tan, and the background colon was fibrotic. Microscopically, the tumor cells showed glandular differentiation characteristic of adenocarcinoma in a background of dense lymphoplasmacytic infiltration with fibrosis and obliterative phlebitis in the pericolic fat tissue. IgG4 immunohistochemical staining showed diffuse positivity in infiltrating plasma cells. The patient was administered adjuvant chemotherapy and prednisolone therapy. The patient's serum IgG4 levels gradually decreased, and a follow-up positron emission tomography-computed tomography scan 1 year after surgery showed no evidence of local or distant recurrence of colorectal cancer. IgG4-RD occurring concurrently with primary colon adenocarcinoma has not been reported. Increased awareness of this rare coexistence can guide clinicians in navigating diagnostic complexities and selecting optimal therapeutic strategies.

Dural tail sign positive tumors: Points to make a differential diagnosis.

Representative patients were treated with total surgical mass resection, and each tumor was histopathologically confirmed to have a secretory meningioma, intradural metastasis of gynecologic origin, and dural metastasis of lung origin. The imaging findings of these patients were inconclusive in differentiating meningioma from metastasis; hence, advanced magnetic resonance imaging (MRI) techniques were considered. Based on these reports, we studied how to differentiate typical meningiomas from atypical and malignant meningiomas and other dura-based malignant tumors using conventional computed tomography and MRI.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Gastrointestinal Follicular Lymphoma: A Single-institutional Experience of 22 Cases With Emphasis on the Comprehensive Clinicopathological Analysis and Diagnostic Re-classification.

BACKGROUND/AIM: Distinguishing gastrointestinal involvement in classic follicular lymphoma (CFL) and duodenal-type follicular lymphoma (DFL) is crucial for proper treatment. This study aimed to describe an integrated diagnostic re-classification of gastrointestinal follicular lymphoma (GIFL) and identify useful features for its differential diagnosis. PATIENTS AND METHODS: We reviewed radiological and endoscopic images and pathology slides of 22 GIFL cases, not otherwise specified. RESULTS: Thirteen cases of duodenal grade 1 FL without nodal disease were re-classified as DFL. Five cases of non-duodenal grade 3 FL accompanied by nodal enlargement were re-classified as CFL. The DFL showed peripherally accentuated CD21 immunoreactivity, whereas the CFL showed strong homogeneous CD21 expression. Four atypical cases were re-classified as DFL and CFL in one and three cases, respectively. CONCLUSION: Our findings support the notion that DFL differs from CFL. In cases of GIFL with atypical features, the possibility of gastrointestinal involvement by CFL should be considered. CD21 expression patterns can assist in the differential diagnosis of CFL and DFL.

Clinicopathological Characterization of Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System.

BACKGROUND/AIM: Primary central nervous system diffuse large B-cell lymphoma (CNS DLBCL) is a rare entity, accounting for 3-4% of intracranial neoplasms. This study aimed to investigate the clinicopathological characteristics of primary CNS DLBCL patients and their prognostic implication. PATIENTS AND METHODS: We collected 74 cases of clinically and pathologically confirmed primary CNS DLBCL from two institutions. Disease-free survival (DFS) and overall survival (OS) were analyzed based on various clinicopathological parameters. RESULTS: Most cases (83.8%) were classified as activated B-cell immunophenotype by Hans algorithm and cell-of-origin classification did not influence the clinical outcome. On univariate analysis, age (>60 years) and ECOG performance status (≥2) were significantly associated with shorter DFS and OS, and MYC/BCL2 co-expression significantly impacted poor DFS. An anaplastic variant was diagnosed in only 2 cases, but it raised possible association with poor outcome. On multivariate analysis, ECOG performance status and age was associated with poor prognosis. CONCLUSION: In primary CNS DLBCL, age and performance status revealed the most significant association with prognosis. Cell-of-origin classification was not a significant prognostic factor in contrast to systemic DLBCL.

Osteosarcoma Arising in Fibrous Dysplasia of the Long Bone: Characteristic Images and Molecular Profiles.

Fibrous dysplasia (FD) is a benign fibro-osseous lesion that frequently involves the craniofacial bones and femur. Malignant transformation of FD is a rare occurrence. We report a 38-year-old woman with osteosarcoma (OS) arising from FD of the femur. Magnetic resonance imaging revealed a well-defined lesion in the medulla of the femur, with cortical thinning and local bone destruction. Wide excision of the femur was performed. Grossly, the inner part of the mass was hard and tan-gray in color, and the outer part of the mass adjacent to the cortex showed myxoid discoloration with infiltrative borders. Microscopically, most of the tumor consisted of curvilinear woven bone and fibrous stroma with bland spindle cells, which transitioned to the outer portion of the tumor, showing cellular proliferation of pleomorphic cells with frequent mitotic activity. Next-generation sequencing revealed GNAS and TP53 mutations, and the diagnosis of OS arising from FD was strongly supported. This case highlights the characteristic images and molecular features of the malignant transformation of FD.

Mesonephric-like Adenocarcinoma of the Uterine Corpus: Comprehensive Analyses of Clinicopathological, Molecular, and Prognostic Characteristics With Retrospective Review of 237 Endometrial Carcinoma Cases.

BACKGROUND/AIM: Uterine mesonephric-like adenocarcinoma (MLA) is a rare malignant tumor of the female genital tract. PATIENTS AND METHODS: We reviewed 237 endometrial carcinoma cases and investigated the clinicopathological and molecular characteristics of uterine MLA. RESULTS: We found that 3.0% (7/237) of the endometrial carcinoma cases were MLAs. Compared to endometrial endometrioid carcinoma, MLA showed larger tumor size, deeper myometrial invasion, increasingly advanced-stage disease, and more frequent lymphovascular space invasion. All MLAs exhibited architectural diversity, compactly aggregated small tubules, eosinophilic intraluminal secretions, overlapped and angulated nuclei, scant cytoplasm, and presence of spindle cells. All the MLAs expressed at least two mesonephric markers. All except one MLA harbored activating Kirsten rat sarcoma viral oncogene homolog mutations. All patients with MLA developed postoperative metastases. MLA had the lowest progression-free survival rate among different histological types of endometrial carcinoma. CONCLUSION: Uterine MLA is a highly aggressive gynecological malignancy, showing unique morphological and molecular features, frequent recurrences and metastases, as well as poor prognosis.

Alveolar Soft Part Sarcoma of the Uterus: Clinicopathological and Molecular Characteristics.

Alveolar soft part sarcoma (ASPS) is a rare malignant mesenchymal tumor mainly affecting adolescents and young adults, with a predilection for the deep soft tissues of extremities. ASPS arising in the female genital tract is extremely rare and poses a significant diagnostic challenge. We herein present two rare cases of ASPS, one occurring in the uterine corpus of a 27-year-old woman, and the other in the uterine cervix of a 10-year-old girl. We described the clinical, histological, immunophenotypical, and molecular characteristics of primary uterine ASPS. We performed immunostaining for transcription factor E3 (TFE3), human melanoma black 45 (HMB45), melan-A, desmin, pan-cytokeratin (CK), paired box 8 (PAX8), CD10, hormone receptors, and S100, and targeted RNA and DNA sequencing using commercially available cancer gene panel. In case 1, a 27-year-old woman was referred to our hospital after laparoscopic uterine myomectomy at an outside hospital. Imaging studies revealed a residual tumor in the uterine corpus. In case 2, a 10-year-old girl underwent surgical excision for the cervical mass and was diagnosed as having ASPS. She was then referred to our hospital for further management. Both patients received total hysterectomy. Histologically, they displayed characteristic histological features of ASPS. Strong nuclear TFE3 immunoreactivity, periodic acid-Schiff-positive, diastase-resistant intracytoplasmic rod-shaped crystalloids or granules, and the identification of ASPSCR1-TFE3 fusion confirmed the diagnosis of ASPS in both cases. Lack of immunoreactivity for HMB45, melan-A, desmin, pan-CK, PAX8, and S100 excluded the possibility of perivascular epithelioid cell tumor, clear cell sarcoma, metastatic renal cell carcinoma, granular cell tumor, and paraganglioma. Our observations can help pathologists make an accurate diagnosis of uterine ASPS and suggest that pathologists should include primary uterine ASPS in the differential diagnosis of uterine mesenchymal tumors.

Diagnostic Challenge in Rapidly Growing Langerhans Cell Histiocytosis with Aneurysmal Bone Cyst in the Maxilla: A Case Report.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by the clonal proliferation of CD1a +/CD 207 + dendritic cells, whose features are similar to those of epidermal Langerhans cells. LCH is more common in children than in adults. Localized osteolytic lesions in the craniofacial bones are the most common manifestations of LCH. However, LCH can also present as a multifocal and multisystem disease with poor prognosis. Locally aggressive LCH needs to be differentiated from various diseases such as osteomyelitis, malignant bone tumors, and soft tissue sarcomas. However, it is difficult to diagnose, since the imaging findings are nonspecific. We report a case of a highly aggressive LCH in the maxilla accompanied by a fluid-fluid level.

Combination of GATA3, SOX-10, and PAX8 in a Comprehensive Panel to Diagnose Breast Cancer Metastases.

BACKGROUND/AIM: It can be difficult to establish the origin of a tumor in metastatic breast cancer (MBC), especially with triple-negative breast cancer (TNBC) or high-grade features. We evaluated the diagnostic utility of GATA3, SOX10, and PAX8 panels in MBC by comparing their expression in each molecular subtype of MBC. PATIENTS AND METHODS: We evaluated 84 MBC and 37 primary TNBC cases using GATA3, SOX10, and PAX8 staining in whole tissue sections. RESULTS: GATA3 was least sensitive in the detection of metastatic TNBC (metastatic non-TNBC, 0.95; metastatic TNBC, 0.37). SOX10 had the lowest overall sensitivity (0.12) but was elevated in metastatic TNBC, even higher than GATA3 (0.59 vs. 0.37). The combination of GATA3, SOX10, and PAX8 expression showed the highest detection rate (MBC, 0.94; metastatic non-TNBC, 0.95; metastatic TNBC, 0.93). CONCLUSION: We recommend combining GATA3, SOX10, PAX8 expression profiling to confirm breast as the site of origin in metastatic MBC.

Radiomic models based on magnetic resonance imaging predict the spatial distribution of CD8+ tumor-infiltrating lymphocytes in breast cancer.

Infiltration of CD8+ T cells and their spatial contexture, represented by immunophenotype, predict the prognosis and therapeutic response in breast cancer. However, a non-surgical method using radiomics to evaluate breast cancer immunophenotype has not been explored. Here, we assessed the CD8+ T cell-based immunophenotype in patients with breast cancer undergoing upfront surgery (n = 182). We extracted radiomic features from the four phases of dynamic contrast-enhanced magnetic resonance imaging, and randomly divided the patients into training (n = 137) and validation (n = 45) cohorts. For predicting the immunophenotypes, radiomic models (RMs) that combined the four phases demonstrated superior performance to those derived from a single phase. For discriminating the inflamed tumor from the non-inflamed tumor, the feature-based combination model from the whole tumor (RM-wholeFC) showed high performance in both training (area under the receiver operating characteristic curve [AUC] = 0.973) and validation cohorts (AUC = 0.985). Similarly, the feature-based combination model from the peripheral tumor (RM-periFC) discriminated between immune-desert and excluded tumors with high performance in both training (AUC = 0.993) and validation cohorts (AUC = 0.984). Both RM-wholeFC and RM-periFC demonstrated good to excellent performance for every molecular subtype. Furthermore, in patients who underwent neoadjuvant chemotherapy (n = 64), pre-treatment images showed that tumors exhibiting complete response to neoadjuvant chemotherapy had significantly higher scores from RM-wholeFC and lower scores from RM-periFC. Our RMs predicted the immunophenotype of breast cancer based on the spatial distribution of CD8+ T cells with high accuracy. This approach can be used to stratify patients non-invasively based on the status of the tumor-immune microenvironment.

Mesonephric-like Adenocarcinoma of the Uterine Corpus: Comprehensive Immunohistochemical Analyses Using Markers for Mesonephric, Endometrioid and Serous Tumors.

Mesonephric-like adenocarcinoma (MLA) of the uterine corpus is a rare but distinct malignant tumor of the female genital tract, demonstrating a characteristic morphology and unique immunohistochemical profiles and molecular alterations. We conducted immunohistochemical staining (IHC) to make precise differential diagnoses of uterine MLAs from common histological subtypes of endometrial carcinomas. We collected 25 uterine MLAs and performed IHC for GATA3, TTF1, CD10, ER, PR, p16, p53, and HER2. Seventeen cases (68.0%) showed at least moderate nuclear GATA3 immunoreactivity in ≥25% of tumor cells. Most cases expressed TTF1 (17/21, 81.0%) and CD10 (luminal; 17/21, 81.0%). Heterogeneous TTF1 expression was noted in 12 cases. An inverse pattern of GATA3 and TTF1 staining was observed in eight cases (32.0%). Three cases (12.0%) showed moderate-to-strong ER expression in ≥25% of tumor cells, and two cases (8.0%) showed moderate-to-strong PR expression in ≥5% of tumor cells. These hormone receptor-positive MLAs varied in intensity and proportion of GATA3 staining. None of the 25 cases exhibited either diffuse and strong p16 expression or aberrant p53 expression. Five cases (20.0%) showed equivocal HER2 immunoreactivity (score 2+), but HER2 FISH confirmed that none of them exhibited HER2 gene amplification. In summary, a small subset of uterine MLAs displayed atypical IHC results: focal but strong expression of ER or PR, the complete absence of GATA3 immunoreactivity, the concurrent expression of mesonephric and hormone receptors, and the inverse pattern of GATA3 and TTF1 staining. These unusual immunophenotypes may complicate the differential diagnosis of MLA. Moreover, pathologists should be encouraged to interpret the IHC results cautiously.