Clinicopathologic and Molecular Characteristics of HER2 (ERBB2)-Altered Non-Small Cell Lung Cancer: Implications for Precision Medicine.

The heterogeneous relationship between protein expression, amplification, and mutations in human epidermal growth factor receptor 2 (HER2) in non-small cell lung cancer (NSCLC) and the optimal methods for detecting these alterations remain unclear. We aimed to elucidate the clinicopathological and molecular characteristics of HER2-altered NSCLC and investigate practical approaches for identifying patients who might benefit from HER2-targeted therapies. Using next-generation sequencing data from 1680 individuals, we searched for patients with HER2-altered NSCLCs, including amplifications and mutations. Clinicopathological data and tissue slides were reviewed. Immunohistochemistry (IHC) and silver in situ hybridization were performed according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Our analysis identified 89 (5.3%) patients with HER2-altered NSCLCs, comprising 30 (1.8%) with amplification and 59 (3.6%) mutations, and they were compared with 165 control patients. Of the 59 HER2-mutated cases, 52 harbored tyrosine kinase domain (TKD) mutations, primarily HER2 exon 20 insertions. HER2 TKD alterations were associated with younger age, female sex, nonsmoking status, adenocarcinoma with a micropapillary pattern, lung-to-lung metastasis, and poor overall survival. The 33 patients with TKD mutations and 3 with non-TKD point mutations showed incomplete or complete membranous HER2 immunoreactivity (1+ and 2+, 61.07%). Six patients exhibiting amplifications had an IHC score of ≤2+ despite their high copy numbers and concomitantly displayed other actionable EGFR, KRAS, SMARCA4, and other HER2 mutations. These HER2-altered NSCLCs with molecular coalterations showed heterogeneous patterns through HER2 IHC and silver in situ hybridization. Therefore, next-generation sequencing should be used to identify HER2 mutations in patients with NSCLC who present with concomitant alterations. In addition, the above clinicopathological characteristics and HER2 IHC results can be valuable determinants for identifying patients with HER2-altered NSCLC. These insights hold promise for the development of more effective diagnostic and therapeutic strategies for this complex subset of NSCLC patients.

Comprehensive Immunohistochemical Analysis of Mesonephric Marker Expression in Low-grade Endometrial Endometrioid Carcinoma.

Immunohistochemical markers shown to be useful in identifying/confirming mesonephric/mesonephric-like differentiation (MLD markers) include thyroid transcription factor (TTF1), GATA-binding protein 3 (GATA3), and cluster of differentiation 10 (CD10). Only a few studies have examined the expression levels of MLD markers in endometrial endometrioid carcinomas (EECs). This study aimed to analyze the frequency and pattern of MLD marker expression in low-grade EECs. We performed immunostaining for the detection of TTF1, GATA3, and CD10 expression in 50 low-grade EEC tissue samples and evaluated their staining proportion and intensity. Nine tumors (18.0%) expressed at least one MLD marker in varying proportions and intensities, and 2 of these tumors were positive for 2 MLD markers (TTF1/GATA3 and GATA3/CD10, respectively). Three (6.0%) tumors showed moderate-to-strong nuclear TTF1 immunoreactivity in ≤5% of the tumor cells. Five tumors (10.0%) had at least moderate nuclear GATA3 staining, and three of them displayed a staining proportion of ≥15%. Three tumors (6.0%) were focal (mean proportion, 15%) but strongly positive for CD10. Our findings indicate that a subset of EEC can express one or more MLD markers with varying staining proportions and intensities. Given that a diagnosis of uterine mesonephric-like adenocarcinoma should be established based on a combination of characteristic histologic features, unique immunophenotypes, and confirmed molecular findings, pathologists should not exclude EEC based only on the presence of focal immunoreactivity for MLD markers. Awareness of the atypical expression patterns of MLD markers in EEC helps pathologists avoid misdiagnosing EEC as a uterine mesonephric-like adenocarcinoma.

Diagnostic Value of Immunostaining for Thyroid Transcription Factor 1 (TTF1) and Paired Box 8 (PAX8) in Distinguishing Pulmonary Metastases of Mesonephric and Mesonephric-like Adenocarcinomas from Primary Lung Adenocarcinomas.

BACKGROUND/AIM: Both mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) express thyroid transcription factor 1 (TTF1). TTF1 is also considered a highly sensitive and specific diagnostic marker for primary lung adenocarcinoma (PLA). However, distinguishing PLA from pulmonary metastatic MA/MLA (PMM) based on the expression of TTF1 alone can be difficult. This study aimed to investigate the expression of TTF1 and paired box 8 (PAX8) and assess their value in distinguishing PMM from PLA. PATIENTS AND METHODS: We reviewed the electronic medical records and pathology slides of eight PMM cases. We conducted immunostaining for TTF1 and PAX8 in 6, 8, and 21 cases of primary MA/MLA, PMM, and PLA, respectively. RESULTS: Two patients with stage IB uterine MLA developed lung metastases at 5 and 57 months after hysterectomy. Solitary pulmonary nodules were suspected to be primary lung cancer in two patients. Compared to primary tumors, all matched PMMs exhibited reduced TTF1 immunoreactivity. In contrast, the majority of PLAs showed uniform and intense TTF1 expression. All except one PMM exhibited diffuse and strong PAX8 expression, while only one PLA showed focal and weak PAX8 expression. CONCLUSION: Immunostaining for TTF1 and PAX8 can help in distinguishing PMM from PLA in the diagnosis of pulmonary lesions detected in patients with a history of MA/MLA.

Neoadjuvant Nivolumab Therapy for Esophageal Squamous Cell Carcinoma: A Single-Arm, Phase II Study.

PURPOSE: Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC. MATERIALS AND METHODS: Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (≤ 10% of residual viable tumor [RVT]). RESULTS: Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; ≤ 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (≥ 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS ≥ 10 (3/8) and 0% in CPS < 10 (0/9). CONCLUSION: Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC.

Thyroid pathology, a clue to PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a hereditary disorder caused by germline inactivating mutations in the PTEN tumor suppressor gene. As a type of PHTS, Cowden syndrome is associated with abnormalities of the thyroid, breast, uterus, and gastrointestinal tract. A 52-year-old-woman visited the outpatient clinic of our endocrinology clinic with multiple thyroid nodules and Hashimoto's thyroiditis. Computed tomography imaging revealed a multinodular mass measuring up to 3.5 cm in the left thyroid lobe, causing laryngotracheal airway displacement. The total thyroidectomy specimen revealed multiple follicular adenomas and adenomatous nodules with lymphocytic thyroiditis and lipomatous metaplasia in the background. The patient was suspected of PTHS based on her thyroid pathology, family history, and numerous hamartomatous lesions of the breast, uterus, and skin. Her diagnosis was confirmed through molecular testing. This case demonstrates that pathologists must be well acquainted with thyroid pathology in PHTS.

Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response.

PURPOSE: Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy. Materials and Methods: We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA. RESULTS: Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10-4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker. CONCLUSION: Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Extraskeletal Mesenchymal Chondrosarcoma of the Uterus.

Mesenchymal chondrosarcoma is an uncommon malignant mesenchymal tumor with an aggressive behavior. Diagnoses of mesenchymal chondrosarcoma are established based on histomorphological, immunohistochemical, and molecular findings. Only one case of extraskeletal mesenchymal chondrosarcoma (EMC) of the uterus has been reported. This article presents the second case of primary uterine EMC, occurring in a 33-year-old woman. We describe the histological and immunophenotypical features of EMC. Our observations will help pathologists and clinicians perform accurate histological diagnoses of uterine EMC and plan appropriate treatment strategies for this rare tumor.

Endocervical Adenocarcinoma: Comprehensive Histological Review and Re-classification of 123 Consecutive Cases According to the Updated World Health Organization Classification of Female Genital Tumors.

BACKGROUND/AIM: The updated 2020 World Health Organization (WHO) classification divides endocervical adenocarcinomas (EACs) into human papillomavirus-associated (HPVA) and -independent (HPVI) tumors. The purpose of this study was to review our EAC cases and re-classify them according to the updated WHO classification. PATIENTS AND METHODS: We reviewed the hematoxylin and eosin-stained slides of 123 EACs and reclassified them according to the updated WHO classification. RESULTS: Eighty-one (65.9%) and 42 (34.1%) patients had HPVA and HPVI EACs, respectively. The usual (60/81; 74.1%) and gastric (31/42; 73.8%) types were the most common HPVA and HPVI EACs, respectively. Signet-ring cell (1/123; 0.8%), invasive stratified mucin-producing (10/123; 8.1%), clear-cell (4/123; 3.3%), mesonephric (3/123; 2.4%), and serous (1/123; 0.8%) types were uncommon. Unusual morphologies were seen, including microcystic, elongated, and fragmented patterns of stromal invasion, micropapillary growth patterns, and gastric-type adenocarcinoma in situ. CONCLUSION: We successfully reclassified all the examined cases based on morphology alone. The numbers and relative proportions of EAC histotypes were variable. We found some uncommon histotypes, as well as unusual but clinically important histological features.

Endometrioid Carcinomas of the Ovaries and Endometrium Involving Endocervical Polyps: Comprehensive Clinicopathological Analyses.

While synchronous ovarian and endometrial endometrioid carcinomas (ECs) have long been described in the literature, ovarian or endometrial EC involving concomitant endocervical polyp (ECP) has not yet been reported. This study aimed to investigate the histological types and prevalence of gynecological tumors co-existing with ECP and to comprehensively analyze the clinicopathological characteristics of ovarian and endometrial ECs involving ECPs. We searched for ECP cases associated with premalignant lesions or malignancies of the female genital tract occurring between March 2019 and February 2022. We then investigated the histological types and prevalence of gynecological tumors co-existing with ECP. In addition, we reviewed electronic medical records and pathology slides to collect the clinicopathological features of four patients with ovarian or endometrial EC involving ECP. We found 429 ECPs over the three-year study period. Of these, 68 (15.9%) were associated with premalignant or malignant lesions occurring in the uterine cervix, endometrium, and ovaries. Four of these cases, including two (0.5%) ovarian grade 3 ECs and two (0.5%) endometrial grade 1 ECs, involved ECPs. In the former cases (cases 1 and 2), ECs involving ECPs exhibited similar morphology and immunohistochemical staining results to those of advanced-stage ovarian EC. In the latter cases (cases 3 and 4), the histological and immunophenotypical features of EC involving ECP were identical to those of primary endometrial EC, despite the lack of tumor involvement in the myometrium, lower uterine segment, and cervical stroma as well as the absence of lymphovascular invasion and lymph node metastasis. In all cases, no evidence of benign endometriosis, endometrial hyperplasia without atypia, or atypical hyperplasia/endometrial intraepithelial neoplasm within ECP or the adjacent endocervical tissue was noted. Considering our results, the involvement of ECP by EC may have been caused by an implantation metastasis from the ovarian (cases 1 and 2) or endometrial (cases 3 and 4) EC. To the best of our knowledge, this is the first exploration of the synchronous occurrence of endometrial or ovarian EC and ECP involvement. Implantation metastasis via transtubal and trans-endometrial cavity migration may have been the pathogenic mechanism of ECP involvement.

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.

A Case of Nasal Cavity and Laryngeal Involvement of Rosai-Dorfman Disease.

Rosai-Dorfman disease (RDD) is a rare non-malignant disorder, characterized by painless multiple cervical lymphadenopathy, fever, and elevated inflammatory markers. Its diagnosis is difficult due to its rare incidence and various clinical presentations, especially in extranodal involvement. In this report, we demonstrate a patient with RDD who presented with a nasal septum and laryngeal tumor that caused dyspnea. We achieved a successful treatment outcome with combined surgical resection of the laryngeal mass and corticosteroid medication. The symptoms and tumors were resolved within 3 weeks after treatment. We reported our experiences with review of literatures.