Distinct Histological Types Research Articles

NCLN as a potential prognosis biomarker in endometrial cancer

Endometrial cancer (ECs) stands as one of the three major malignancies impacting females globally, with its incidence steadily increasing. ECs can be categorized into two types based on their clinicopathological features. Type I ECs typically exhibit low stage, favorable histological types, and low histological grade, correlating with a more favorable prognosis. Conversely, Type II ECs present with advanced-stage disease, aggressive behavior, and poorer histological types, resulting in a worse prognosis.The expression level of progesterone receptors (PR) holds significant importance in determining the prognosis of patients with ECs. Elevated levels of PR are linked to a more favorable prognosis, primarily attributed to progesterone's inhibitory influence on cancer cell proliferation and invasion. Moreover, progesterone promotes cell cycle inhibition through its regulation of PR, further contributing to improved outcomes in ECs.Nicalin (NCLN) plays a crucial role in facilitating the translocation of multichannel membrane proteins to the endoplasmic reticulum membrane and is implicated in embryonic development. Structurally akin to NODAL Modulator (NOMO), NCLN antagonizes NOMO during embryogenesis, forming a complex that antagonizes the Nodal pathway, thereby influencing mesoderm development. However, the precise relationship between NCLN and ECs remains incompletely understood.Our research findings reveal that NCLN actively stimulates the proliferation of ECs cells and exhibits a positive correlation with PR, albeit without impacting ER. Moreover, the expression levels of NCLN in ECs demonstrate associations with distinct histological types. These observations suggest that NCLN could emerge as a promising marker in the histological classification of ECs.

Unravelling the molecular landscape of endometrial cancer subtypes: insights from multiomics analysis.

Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multiomics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. Two-sample mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and nonendometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. The authors identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and nonendometrioid EC, and 125 causal relationships between plasma proteins and nonendometrioid EC were observed. Substantial differences were observed between endometrioid and nonendometrioid histological types of EC at both the metabolite and protein levels. The authors identified seven overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and six overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in nonendometrioid subtype and conducted network analysis of above proteins and metabolites to identify coregulated nodes. Our findings observed substantial differences between endometrioid and nonendometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.

Adjuvant Therapy for Endometrial Cancer in the Era of Molecular Classification

ABSTRACT Endometrial cancer primarily undergoes surgical intervention, with adjuvant treatments such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined therapy investigated in randomized trials. Treatment decisions hinge on clinicopathological risk factors. Low-risk cases usually require surgery alone, whereas high-intermediate risk often benefit from adjuvant vaginal brachytherapy for enhanced local control with minimal side effects. Recent trials advocate pelvic radiotherapy for high-risk cases, particularly in Stage I–II tumors with risk factors. Chemoradiation proves advantageous for serous cancers and Stage III disease, improving recurrence-free, and overall survival. Molecular studies, notably the Cancer Genome Atlas project, identified four distinct molecular classes, transcending stages, and histological types. These molecular subtypes exhibit a stronger prognostic impact than histopathological characteristics, heralding a shift toward molecular-integrated diagnostics and treatments. Incorporating molecular factors into adjuvant strategies, including targeted therapies, marks a new paradigm in endometrial cancer management, underpinning ongoing research, and clinical trials. This review outlines current adjuvant approaches, underscores the emergence of molecular-integrated risk profiling, and touches on developments in targeted therapy.

Collision Lesions in Head and Neck Area: A Retrospective Study of 97 Reported Cases

Background: Collision (hybrid) lesions consist of two or more distinct histologic types occurring separately but within the same area. This review focuses on discussing all related and available case reports of hybrid lesions in the head and neck area. Methods: The literature was searched using several databases, including Scopus, Web of Science, PubMed, and Google Scholar. Papers published from 1990 to 2022 with full text available were considered for inclusion in the study. For a more comprehensive understanding, all lesions were categorized into cutaneous, jaw, and salivary gland groups and lesions in miscellaneous tissues. Results: In general, 97 reported collision lesions developed in the head and neck region. Among them, 31 (32%) and 34 (35%) cases were cutaneous hybrid lesions and in the jaws, respectively. In addition, 27 (27.8%) and 5 (5.1%) cases were in salivary glands and miscellaneous tissues, respectively. Conclusion: While the presence of true hybrid tumors is well-established, some reported cases have prompted researchers to categorize them as biphasic differentiations. The rarity of these cases contributes to limited knowledge regarding their clinical behavior, prognosis, and optimal treatment. It is crucial to emphasize the characteristic and potentially perplexing histological appearances.

Safety and preliminary efficacy of EIK1001 in combination with atezolizumab in participants with advanced solid tumors.

2618 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-102 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 combined with atezolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with atezolizumab (1200 mg Q3W). Results: Forty-one pts (median age 65 years [range = 32 to 79]) with multiple, distinct histological tumor types and a median of 3 prior Rx regimens were enrolled. Overall, a total of 28/41 (68.3%) receiving EIK1001 + atezolizumab experienced a treatment-related adverse event (TRAE). Of these, 4/41 (9.8%) experienced a ≥ Grade 3 TRAE, including fatigue, nausea, hyponatremia, and lymphedema. Only 1/41 (2.4%) experienced manageable cytokine release syndrome. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 37), complete response (CR) or partial response (PR) was observed for 3/37 (8.1%). Disease control (including CR, PR, or stable disease) was observed in 19/37 (51.4%). The median duration of response (DOR) was 13 months (range = 10 to 27). One responder was PD-L1 negative yet had a > 12-month DOR; another had a history of prior anti-PD-1 Rx yet experienced a 10-month DOR on comb Rx. EIK1001 PK was linear and dose-proportional, and was not affected by combination with atezolizumab. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with atezolizumab. Responses were observed even in pts not anticipated to respond to atezolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT04196530 .

Advancing drug development by leveraging microdissection for proteogenomic analysis of histological sections.

e14660 Background: Combining laser capture microdissection (LCM) with proteogenomics in cancer research offers a targeted way to way to explore the intricate interactions between the tumor microenvironment and tumor cells proper. For immuno-oncology (IO) research, this is especially important, since improvements in the predictability of patient response to IO-based drugs is greatly needed. An improved understanding of the spatial relationships involving tumor cells, stromal cells, blood supply and immune cell interactions may help to inform drug development and improve the indicators of success for IO-based drug regimens. Methods: From fresh frozen tissue, LCM is used to isolate and obtain distinct histological cell types. Nucleic acids and proteins are extracted from captured cells for in-depth multi-modality molecular profiling assays. This includes multiple genomic modalities and a customized solution-based mass spectrometry proteomics approach for samples or specimens with a limited amount of tissue. Results: Optimizing the analysis of minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, DNA sequencing can be performed for the discovery and analysis of actionable mutations, copy number variation, and methylation profiles. RNA-seq may be performed for gene expression. Regarding genomic-based studies, commercial kits are often utilized for these steps due to their general availability, rapid innovation, and the robust performance of these products. However, this kit-based adaptive approach is not true for proteomics. There remains a need for highly sensitive proteomic methods targeting small-sized samples. Our novel proteogenomics approach is focused around a customized enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. This includes an in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling. Conclusions: A proteogenomic approach is reported that is utilizing amount limited tissue quantities from microdissected fresh frozen tissue. The methodology may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume.

Safety and preliminary efficacy of EIK1001 in combination with pembrolizumab in participants with advanced solid tumors.

2521 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-101 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 as either monotherapy (mono Rx; previously reported) or combined with pembrolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During comb Rx dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with pembrolizumab (200 mg Q3W). Results: Fifty-one pts (median age 67 [range 33 to 86]) with multiple, distinct histological tumor types and with a median of 3 prior Rx regimens were enrolled. Overall, a total of 42/51 (82.4%) comb Rx pts experienced a treatment-related adverse event (TRAE). A total of 9/51 (17.7%) experienced a ≥ Grade 3 TRAE, including fatigue, cytokine release syndrome (CRS), hemiparesis, hypertension, joint range of motion reduced, muscular weakness, pancreatitis, rash (maculopapular), skin plaque, and stomatitis. Overall, 5/51 (9.8%) experienced manageable CRS, with only 1 discontinuation due to CRS. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 50), complete response (CR) or partial response (PR) was observed for 7/50 (14.0%), including 3 CR and 4 PR. Disease control (including CR, PR, or stable disease) was observed in 24/50 (48.0%). The median duration of response was 10 months (range = 4 to 32 months). Responses were observed in pts with prior anti-PD-1 exposure as well as in those with low or negative PD-L1 tumor expression. EIK1001 PK was linear and dose-proportional, and combination with pembrolizumab did not affect EIK1001 PK. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with pembrolizumab. Responses were observed even in heavily pretreated patients not anticipated to respond to pembrolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT03486301 .

Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features.

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy.

Abstract 730: Leveraging microdissection for proteogenomic analysis of histological sections to advance drug development

Abstract Background: Combining proteogenomics with laser capture microdissection (LCM) in cancer research offers a targeted way to explore the intricate interactions between tumor cells and the tumor microenvironment. This is especially important for immuno-oncology (IO) research where improvements in the predictability of patient response to IO-based drugs is sorely needed. An improved understanding of the spatial relationships involving tumor cells proper, stromal cells, blood supply and immune cell interactions may help to inform drug development and improve the indicators of success for IO-based drug regimens. Methods: LCM is used to isolate and obtain distinct histological cell types from fresh frozen tissue. Once cells have been captured, nucleic acids and proteins are extracted for in-depth multi-modality molecular profiling assays involving multiple genomic modalities and a customized solution-based mass spectrometry proteomics approach for samples or specimens with a limited amount of tissue. Results: Optimizing analysis of minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, RNA-seq may be performed for gene expression and DNA sequencing performed for the discovery and analysis of actionable mutations, copy number variation, and methylation profiles. Regarding genomic-based studies, commercial kits are often utilized for these steps due to their general availability, rapid innovation, and the robust performance of these products. However, this kit-based adaptive approach is not true for proteomics. There remains a need for highly sensitive proteomic methods targeting small-sized samples. A significant part of our proteogenomics approach is focused around an enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. This includes an in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling. Conclusions: Reported here is a proteogenomic approach that is leveraging from microdissected fresh frozen tissue. The methodology may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume. Citation Format: Ik Jae Shin, Michael Tangrea, Michael R. Emmert-Buck, Donald J. Johann. Leveraging microdissection for proteogenomic analysis of histological sections to advance drug development [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 730.

Clinicopathological and endoscopic features of Helicobacter pylori infection-negative gastric cancer in Japan: a retrospective study.

Helicobacter pylori infection-negative gastric cancer (HPNGC) has not been systematically investigated in consecutive patients. Hence, this study aimed to investigate the clinicopathological and endoscopic features of HPNGC. This single-center retrospective study selected participants from patients with gastric cancer who were treated at the Fukuoka University Chikushi Hospital between January 2013 and December 2021. Only patients diagnosed with HPNGC were enrolled, and their clinicopathological and endoscopic features were analyzed in detail. The prevalence of HPNGC in the present study was 2.6% (54/2112). The types of HPNGC observed in each gastric region were as follows: advanced gastric cancer was observed in the cardia; gastric adenocarcinoma of fundic-gland differentiation, gastric adenocarcinoma of foveolar-type presenting with whitish elevation and raspberry-like foveolar-type gastric adenocarcinoma, gastric adenocarcinoma arising in polyposis, and gastric adenocarcinoma with autoimmune gastritis were observed in the fundic gland region ranging from the gastric fornix to the gastric body; signet-ring cell carcinoma was observed in the gastric-pyloric transition region ranging from the lower gastric body to the gastric angle; and well-differentiated tubular adenocarcinoma with low-grade atypia was observed in the antrum. This study revealed that tumors from each gastric region exhibited distinct macroscopic and histological types in HPNGC.

METAPLASTIC CARCINOMA BREAST: A CASE SERIES

Introduction: Metaplastic breast carcinoma is a distinct histological type of breast cancer and comprises of two components ofboth epithelial & mesenchymal type in a single tumor. It includes adenosquamous, squamous cell carcinoma (SCC), spindle cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, mixed carcinoma and myoepithelial carcinoma. Materials and Methods: The study comprises of 5 cases of Metaplastic Breast carcinoma and was conducted in the Department of Pathology in Western part of India. Discussion: MBC is characterized by adenocarcinoma admixed with spindle cells, squamous cells and mesenchymal differentiation. Among the five cases in the present series, two cases showed lymph nodes metastasis. Commonlyimmunohistochemistry (IHC) markers in cases of MBC shows triple negative for estrogen receptor (ER), progesterone receptor (PR) and HER2-neu. Conclusion: The MBC has a poor prognosis and have a diverse clinical behavior, variable histology and different regime of treatment.

A Microdissection Protocol for Proteogenomic Analysis of Histological Sections to Advance Drug Development.

Combining proteogenomics with laser capture microdissection (LCM) in cancer research offers a targeted way to explore the intricate interactions between tumor cells and the different microenvironment components. This is especially important for immuno-oncology (IO) research where improvements in the predictability of IO-based drugs are sorely needed, and depends on a better understanding of the spatial relationships involving the tumor, blood supply, and immune cell interactions, in the context of their associated microenvironments. LCM is used to isolate and obtain distinct histological cell types, which may be routinely performed on complex and heterogeneous solid tumor specimens. Once cells have been captured, nucleic acids and proteins may be extracted for in-depth multimodality molecular profiling assays. Optimizing the minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, RNA-seq may be performed for gene expression and DNA sequencing performed for the discovery and analysis of actionable mutations, copy number variation, methylation profiles, etc. However, there remains a need for highly sensitive proteomic methods targeting small-sized samples. A significant part of this protocol is an enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. Included is a detailed in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling. Described is a proteogenomic approach leveraged from microdissected fresh frozen tissue. The protocols may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume.

Metachronously Occurring Carcinomas of Different Histological Types in Bilateral Parotid Glands.

The occurrence of multiple malignant tumors with varying histological characteristics in bilateral parotid glands has never been documented previously in the literature. Here, the authors present a noteworthy case of a patient who exhibited the sequential development of primary carcinomas, each displaying distinct histologic types within the bilateral parotid glands. This case concerns a 57-year-old male patient who initially underwent surgery, followed by adjuvant radiotherapy, for squamous cell carcinoma diagnosed in the right parotid gland. Approximately 3 years after this treatment, a novel salivary duct carcinoma emerged within the left parotid gland, prompting a second round of surgical intervention, again followed by adjuvant radiotherapy. Subsequently, a recurrent tumor was identified within the left Stensen duct, necessitating additional surgical intervention. While monitoring for recurrence or metastases remains an important aspect of post-treatment care for salivary gland cancer, it is also imperative to consider the potential for developing a second primary salivary gland cancer.

Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes-Obesity as a Crucial Player.

Breast cancer is a heterogeneous entity, where different molecular subtypes (MS) exhibit distinct prognostic and therapeutic responses. A series of 62 breast cancer samples stratified by MS was obtained from the tumor biobank of IPO-Porto. The expression of glycolysis and gluconeogenesis-regulating enzymes was investigated by immunohistochemistry. Data analysis included stratification according to MS, body mass index (BMI), and BMI with MS (mBMI). We observed significant differences in pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PCK), and fructose-1,6-bisphosphatase (FBP) tumor cell expression when stratified by MS and mBMI. The expression of these enzymes was also statistically dependent on hormonal receptors and HER2 status and correlated with pathological stage and histological grade. Obesity tended to attenuate these differences, particularly in PC expression, although these were not affected by adipocyte deposition or inflammatory infiltration at the tumor microenvironment. Nonetheless, PCK and FBP expression was also modified by the presence of obesity-associated disorders like diabetes, hypertension, and dyslipidemia. Taken together, these findings identify metabolic fingerprints for breast cancer as distinct histological types, which are affected by the presence of obesity and obesity-associated conditions. Despite the biological role of the differential expression of enzymes remaining unknown, the current study highlights the need to identify the expression of gluconeogenic-regulating enzymes as a tool for personalized medicine.

Primary mucinous cystadenocarcinoma of breast with sternal metastasis: A diagnostic challange

The WHO categorizes the breast tumors in various distinct histological types based on cell morphology and architecture. A widely accepted fact that the aggressive nature of the breast cancer can be determined by its histological type, grade, nodal status, and metastasis holds the ground even in the era of immunohistochemistry (IHC) and molecular. An extremely rare variant of primary breast carcinoma belongs to the family of mucin producing carcinoma sharing the same histology as the mucinous cystadenocarcinoma of the ovary and pancreas. The tumour typically occurs in postmenopausal women with a median patient age of 61 years. Due to the rarity of these tumors, there is an extreme paucity of literature on this topic. We report a case of 35 year old female with left breast lump and presternal swelling. Breast lumpectomy and total sternectomy was done and final diagnosis was given as Primary mucinous cystadenocarcinoma with sternal metastasis and Estrogen receptor (ER) and Progesterone receptors (PR) positivity.

Clinical perspectives of rare ovarian tumors: clear cell ovarian cancer.

Ovarian clear cell carcinoma (OCCC) is a rare and distinct histological type of epithelial ovarian carcinoma in terms of its histopathological, clinical and genetic features. Patients with OCCC are younger and diagnosed at earlier stages than those with the most common histological type-high-grade serous carcinoma. Endometriosis is considered a direct precursor of OCCC. Based on preclinical data, the most frequent gene alternations in OCCC are mutations of AT-rich interaction domain 1A and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. The prognosis of patients with early-stage OCCC is favorable, whereas patients at an advanced stage or who have the recurrent disease have a dismal prognosis due to OCCC's resistance to standard platinum-based chemotherapy. Despite a lower rate of response due to its resistance to standard platinum-based chemotherapy, the treatment strategy for OCCC resembles that of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and adjuvant platinum-based chemotherapy. Alternative treatment strategies, including biological agents based on molecular characteristics specific to OCCC, are urgently needed. Furthermore, due to its rarity, well-designed collaborative international clinical trials are needed to improve oncologic outcomes and the quality of life in patients with OCCC.

Genetic alteration and ctDNA mutation profiling of esophageal cancer in Chinese patients.

e16046 Background: Esophageal cancer is the sixth most common cause of cancer-related mortality. There are two distinct histological types of esophageal cancer: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). In China, ESCC is the major subtype. Higher incidence of EAC is observed in western countries. Liquid biopsy detecting circulating tumor DNA is a non-invasive, real-time and highly sensitive approach that is able to identify and monitor the genetic mutations in tumor. Methods: In this study, we collected 490 Chinese esophageal cancer patients from 2018-2022 and characterized the mutational landscape of esophageal tumor tissue and circulating tumor DNA by whole exome sequencing or deep sequencing of targeted gene panel. The consistency of genetic alteration between tumor and ctDNA was also explored. Results: A total of 176 patients with plasma and 345 patients with cancer tissue were analyzed, among them, 31 patients had both ctDNA and tissue biopsy data. 277 genes with 1257 mutations were identified from plasma samples of 176 patients. The top frequently mutated genes were TP53 (89.1%), KMT2D (24.0%), SYNE1 (14.9%), NOTCH1 (14.3%), EP300 (13.7%), LRP1B (13.7%) and ZNF750 (10.3%). The mutation rates of these genes between ctDNA and tissue biopsy (N = 31 patients) were in concordance by Fisher's exact test (P > 0.05). Most frequent mutations were found in TP53 gene, which account for 89.1% of total plasma samples and 90.4% of tumor tissues. KMT2D gene mutations were detected in 24% of patients which encode histone methyltransferase that methylates the Lys-4 position of histone H3 and regulates transcriptional activation, indicating epigenetic regulation might be involved in the pathogenesis of esophageal cancer. Functional enrichment analysis was performed including Gene Ontology (GO) and KEGG analysis across all the three domains, Biological process, Molecular Function, and Cellular component. The KEGG terms with the highest enrichment score were PI3K−Akt signaling pathway, which is a key driver in carcinogenesis. In addition, we didn’t observe the mutually exclusive mutation or co-occurrence pattern of any gene pairs in our cohort. Conclusions: We demonstrated the utility of liquid biopsy to draw a ctDNA mutation profiling of esophageal cancer in Chinese patients. Genetic mutations identified from ctDNA showed consistency with mutations from tumor tissue.

Collision Tumors of the Thyroid

"Collision tumors, rare neoplasms underlying two distinct histological types of carcinomas (with different origins) separated by normal tissue, are described in many organs including the thyroid gland, but to a lesser extent. We aim to overview the current published data concerning collision tumors of the thyroid (CTT). This is a narrative review considering papers published on PubMed through a search starting from the terms “collision” and “thyroid”. Inclusion criteria are full-length articles, the English language, the timeline from inception to December 2022, and original studies with different levels of statistical evidence. We followed the main types of thyroid carcinomas: differentiated thyroid carcinoma of papillary and follicular type, anaplastic/ undifferentiated/poorly differentiated carcinoma, respectively medullary thyroid carcinoma. We identified 92 papers based on the mentioned key words criteria. We excluded 54 papers (reviews or non-thyroid CTT or other topics outside our purpose). We included in the final analysis 38 papers: 34 case reports (1 patient per paper), 2 case series (2 individuals per each article), one case series of 3 subjects, and a single study of retrospective type (including 21 subjects) – a total of 62 patients on published cases which represents the largest study on published cases to our knowledge (according to our methodology) "

Bronchiolar adenoma with squamous metaplasia: a distinct phenotype.

Pulmonary bronchiolar adenoma is a benign lung tumour characterised by nodular proliferation of bilayered bronchiolar-type epithelium with a continuous layer of basal cells. The aim of this study was to describe a distinct and rare histological type of pulmonary bronchiolar adenoma: bronchiolar adenoma with squamous metaplasia. We examined the clinicopathological, immunohistochemical, and molecular characteristics of five cases (two cases from the same patient). The samples were histopathologically characterised by bilayered bronchiolar-type cells with sheets like spindle-oval and polygonal cells. Immunohistochemistry analysis revealed that columnar surface cells of the tumour were diffusely positive for TTF-1 and Napsin A, while basal cells were positive for P40 and P63. Moreover, the squamous metaplastic cells in the stroma were positive for P40, and P63, while being negative for TTF-1, Napsin A, S100, and SMA. Genomic analyses uncovered that all five samples had BRAF V600E mutations. Notably, both squamous metaplastic and basal cells were positive for BRAF V600E staining. We discovered a distinct subtype of pulmonary bronchiolar adenoma termed bronchiolar adenoma with squamous metaplasia. It is composed of columnar surface cells, basal cells, and sheet-like spindle-oval cells with squamous metaplasia in the stroma. All five samples harboured the BRAF V600E mutation. Importantly, BASM may be misdiagnosed as pulmonary sclerosing pneumocytoma upon frozen sections analysis. It may need further immunohistochemistry staining.

Castleman’s disease associated with bronchopulmonary cancer

Castleman’s disease is a rare lymphoproliferative disease of unknown etiology. It presents itself under different clinical pathological entities, with mainly two distinct histological types, the hyaline-vascular type and the plasmocytic type, and two distinct clinical forms, the localized unicentric form, which generally has a favorable prognosis, and the diffuse multiricentric form, with prognosis often pejorative, justified by the emergence of certain malignant tumors during its evolution. The association with bronchopulmonary cancer has rarely been reported in the literature, and explanations other than coincidence remain very probable. The authors report two rare cases of multicentric Castleman’s disease associated with bronchopulmonary cancer.