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Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods: For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results: The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions: The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well‐characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune‐related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor‐infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor. [ABSTRACT FROM AUTHOR]

Abstract Background We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/ ) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.

Cancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well‐characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune‐related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor‐infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor.

Identifying the primary site of origin of metastatic cancer is vital for guiding treatment decisions, especially for patients with cancer of unknown primary (CUP). Despite advanced diagnostic techniques, CUP remains difficult to pinpoint and is responsible for a considerable number of cancer-related fatalities. Understanding its origin is crucial for effective management and potentially improving patient outcomes. This study introduces a machine learning framework, ONCOfind-AI, that leverages transcriptome-based gene set features to enhance the accuracy of predicting the origin of metastatic cancers. We demonstrate its potential to facilitate the integration of RNA sequencing and microarray data by using gene set scores for characterization of transcriptome profiles generated from different platforms. Integrating data from different platforms resulted in improved accuracy of machine learning models for predicting cancer origins. We validated our method using external data from clinical samples collected through the Kangbuk Samsung Medical Center and Gene Expression Omnibus. The external validation results demonstrate a top-1 accuracy ranging from 0.80 to 0.86, with a top-2 accuracy of 0.90. This study highlights that incorporating biological knowledge through curated gene sets can help to merge gene expression data from different platforms, thereby enhancing the compatibility needed to develop more effective machine learning prediction models.

Abstract Background Cancer of unknown primary (CUP) is an orphan disease generally presented by undifferentiated and aggressive morphological phenotype. The treatment of CUP is solely dependent upon the origin of cancer. Despite extensive diagnostic testing, in most of the cases the primary site remains unidentifiable. Case presentation This case demonstrates a 75-year-old male patient, who initially presented with the complaints of swelling over right side of the neck since 2 months. A cervical lymph node biopsy was taken for immunohistochemistry, which revealed cytokeratin (CK) and CK7 markers to be positive. Computerized tomography (CT) of Thorax showed subcentimetric subpleural nodules in bilateral lungs fields, predominantly in lower lobes (metastatic in nature). A subsequent pulmoCORE 12 gene panel test was recommended, and patient was discharged with tablet gefitinib 250mg and capsule containing vitamins plus minerals. After one month, patient revisited with the pulmoCORE 12 gene test report which revealed polymorphism in TP53. A pathogenic variant of tumor protein p53 (TP53), i.e., p.Glu198Ter (amino acid alteration) and c.592G > T (coding) variant, was detected, which has 17.2% variant allele frequency. There are no treatment guidelines for TP53 mutation; therefore, the patient was treated with injection paclitaxel 70mg and carboplatin 100mg for 12 cycles along with palliative radiotherapy of 20 Gy for 5 fractions. The overall prognosis of patient was found to be favorable. Conclusions There is a need for development of comprehensive guidelines and new molecularly targeted therapies for treatment of CUP which can be tailored for each patient and achieve precise therapeutic outcome.

Introduction: Cancers of unknown primary are aggressive and rare malignancies with a complex diagnosis and management. Here we present a case in which imaging, pathology, and molecular biology did not match for a specific tumor site and the importance of a multidisciplinary team for these complicated cases. Case Presentation: A man in his 70s with strong smoking history under workup for suspicion of metastatic lung cancer underwent lung mass biopsy. Immunohistochemical stains corresponded to hepatocellular/cholangiocarcinoma or germ cell tumor; however, dedicated liver and testicular studies including imaging and iscochrome 12p FISH were negative. Additionally, somatic variant profiling was not specific for any malignancy nor targetable variants. Given the pattern of disease, risk factors, and patient history, the patient received treatment for lung adenocarcinoma (carboplatin, pemetrexed, and pembrolizumab). The patient had a drastic improvement in dyspnea, weight gain, and was able to return to work. Conclusion: This report describes a case in which immunohistochemistry and molecular profiling did not identify the tissue of origin and highlights the importance of a multidisciplinary team to reach a diagnosis and guide treatment without delaying patient care in patients with these diagnoses.

Background: Cancer of unknown primary (CUP) is an orphan disease generally presented by undifferentiated and aggressive morphological phenotype. The treatment of CUP is solely dependent upon the origin of cancer. Despite extensive diagnostic testing, in most of the cases the primary site remains unidentifiable. Case presentation: This case demonstrates a 75-year-old male patient, who initially presented with the complaints of swelling over right side of the neck since 2 months. A cervical lymph node biopsy was taken for immunohistochemistry, which revealed cytokeratin (CK) and CK7 markers to be positive. Computerized tomography (CT) of Thorax showed subcentimetric subpleural nodules in bilateral lungs fields, predominantly in lower lobes (metastatic in nature). A subsequent pulmoCORE 12 gene panel test was recommended, and patient was discharged with tablet gefitinib 250mg and capsule containing vitamins plus minerals. After one month, patient revisited with the pulmoCORE 12 gene test report which revealed polymorphism in TP53. A pathogenic variant of tumor protein p53 (TP53), i.e., p.Glu198Ter (amino acid alteration) and c.592G > T (coding) variant, was detected, which has 17.2% variant allele frequency. There are no treatment guidelines for TP53 mutation; therefore, the patient was treated with injection paclitaxel 70mg and carboplatin 100mg for 12 cycles along with palliative radiotherapy of 20 Gy for 5 fractions. The overall prognosis of patient was found to be favorable. Conclusions: There is a need for development of comprehensive guidelines and new molecularly targeted therapies for treatment of CUP which can be tailored for each patient and achieve precise therapeutic outcome. [ABSTRACT FROM AUTHOR]

Introduction: Cancers of unknown primary are aggressive and rare malignancies with a complex diagnosis and management. Here we present a case in which imaging, pathology, and molecular biology did not match for a specific tumor site and the importance of a multidisciplinary team for these complicated cases. Case Presentation: A man in his 70s with strong smoking history under workup for suspicion of metastatic lung cancer underwent lung mass biopsy. Immunohistochemical stains corresponded to hepatocellular/cholangiocarcinoma or germ cell tumor; however, dedicated liver and testicular studies including imaging and iscochrome 12p FISH were negative. Additionally, somatic variant profiling was not specific for any malignancy nor targetable variants. Given the pattern of disease, risk factors, and patient history, the patient received treatment for lung adenocarcinoma (carboplatin, pemetrexed, and pembrolizumab). The patient had a drastic improvement in dyspnea, weight gain, and was able to return to work. Conclusion: This report describes a case in which immunohistochemistry and molecular profiling did not identify the tissue of origin and highlights the importance of a multidisciplinary team to reach a diagnosis and guide treatment without delaying patient care in patients with these diagnoses. [ABSTRACT FROM AUTHOR]

Background: Tumor tissue origin detection is of great importance in determining the appropriate course of treatment for cancer patients. Classifiers based on gene expression and DNA methylation profiles have been confirmed to be feasible and reliable to predict the tumor primary. However, few works have been performed to compare the performance of these classifiers based on different profiles. Methods: Using gene expression and DNA methylation profiles from The Cancer Genome Atlas (TCGA) project, eight machine learning methods were employed for the tumor tissue origin detection. We then evaluated the predictive performance using DNA methylation, mRNA, microRNA (miRNA) and long non-coding RNA (lncRNA) expression profiles in a comparative manner. A statistical method was introduced to select the most informative CpG sites. Results: We found that LASSO is the most predictive models based on various profiles. Further analyses indicated that the results derived from DNA methylation (overall accuracy: 97.77%) are better than those derived from mRNA expression (overall accuracy: 88.01%), microRNA expression (overall accuracy: 91.03%) and lncRNA expression (overall accuracy: 95.7%). It has been suggested that we can achieve an overall accuracy >90% using only 1,000 methylated CpG sites for prediction. Conclusion: In this work, we comprehensively evaluated the performance of classifiers based on different profiles for the tumor origin detection. Our findings demonstrated the effectiveness of DNA methylation as biomarker for tracing tumor tissue origin using LASSO and neural network. [ABSTRACT FROM AUTHOR]

Background Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required. Methods Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology. Next-generation sequencing (NGS) included targeted panels. Statistical analyses were conducted with R Software 4.2.2. Results A total of 44 patients were included. With a median follow-up of 39.46 months (interquartile range [IQR] 35.98-47.41 months), median PFS (mPFS) to first-line regimen was 3.98 months (95% CI 3.22-5.98), with a clinical benefit rate of 26% (95% CI 14%-49%), and disease control rate (DCR) limited to 48.28%. Most patients (26 of 31, 83.87%) received platinum-doublet chemotherapy, with no statistically significant difference between first-line treatment regimens. Median OS (mOS) was 18.8 months (95% CI 12.3-39.9), with a 12-month OS rate of 66% (95% CI 50%-85%). All patients received comprehensive genomic profiling (CGP). For 11 patients, NGS was unsuccessful due to low sample quantity and/or quality. For the remaining, TP53 (n  = 16, 48%) and KRAS (n  = 10, 30%) represented the most altered (alt) genes. No microsatellite instability was observed (0 of 28), while 6 of 28 (21.43%) tumors carried high TMB (≥10 mutation per megabase). Eight of 33 tumors (24.2%) displayed at least one actionable alteration with potential clinical benefit according to ESCAT. Only 2 of them received targeted therapy matched to genomic alterations, with a combined mPFS of 2.63 months (95% CI 1.84-not evaluable) as third-line regimens. Six patients received anti-PD1/PD-L1 therapy, showing a meaningful mPFS of 13 months (95% CI 2.04-not evaluable). Conclusion CUP exhibits poor prognosis with limited benefits from standard treatment regimens. A significant proportion of CUPs carry actionable alterations, underscoring the importance of genomic profiling to gather additional treatment opportunities. In addition, immunotherapy might represent a valuable treatment option for a subset of CUP. Finally, accurate definition of sequencing methods and platforms is crucial to overcome NGS failures. [ABSTRACT FROM AUTHOR]

Purpose: Axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary (CUPAx) is a rare disease in women. This retrospective study intended to examine the clinicopathological features of CUPAx and compared CUPAx genetically with axillary lymph node metastases from breast cancer (BCAx), investigating differences in their biological behavior. Methods: We conducted the clinical and prognostic analysis of 58 CUPAx patients in West China Hospital spanning from 2009 to 2021. Gemonic profiling of 12 CUPAx patients and 16 BCAx patients was conducted by the FoundationOne CDx (F1CDx) platform. Moreover, we also compared the gene mutation spectrum and relevant pathways between the two groups and both TCGA and COSMIC databases. Results: The majority of the 58 CUPAx patients were HR-/HER2- subtype. Most patients received mastectomy combined radiotherapy (50 Gy/25f). CUPAx patients who received mastectomy instead of breast-conserving surgery had a more favorable overall prognosis. Radiotherapy in chest wall/breast and supraclavicular/infraclavicular fossa was the independent prognostic factor (HR = 0.05, 95%CI = 0.00–0.93, P = 0.04). In 28 sequencing samples (CUPAx, n = 12, BCAx, n = 16) and 401 TCGA-BRCA patients, IRS2 only mutated in CUPAx (33.33%) but amplified in BCAx (11.11%) and TCGA-BRCA (1.5%). Pathway analysis revealed that BCAx had more NOTCH pathway mutations than CUPAx. Enrichment analysis showed that CUPAx enriched more in mammary development and PML bodies than BCAx, but less in the positive regulation of kinase activity. Conclusions: More active treatment methods, like chemotherapy, mastectomy and postoperative radiotherapy, could improve the prognosis of CUPAx. The differential mutation genes of CUPAx and BCAx might be associated with their respective biological behaviors like invasiveness and prognosis. [ABSTRACT FROM AUTHOR]

Background/Aim: Membranous nephropathy (MN) is a nephrotic syndrome with both idiopathic and secondary etiologies. The mechanism of cancer-associated MN is presumed to involve the immunological production of antibodies against a tumor antigen, although little is known about the detailed mechanism. Lung cancer is a major neoplasm associated with cancer-associated MN. However, the simultaneous occurrence of secondary MN in patients with cancer of unknown primary (CUP) remains unclear. Case Report: Here, we present a case of secondary MN in a 72-year-old female as a paraneoplastic syndrome in CUP. Thoracic radiotherapy up to a total of 60 Gy was initially performed on the right subclavian and mediastinal lymph nodes. Computed tomography revealed marked shrinking of these lymph nodes, and the secondary MN also improved without any symptoms. Conclusion: The presence of proteinuria in patients with CUP suggests the possibility of secondary MN as a rare differential diagnosis. [ABSTRACT FROM AUTHOR]

Background: Cancer of unknown primary (CUP) is difficult to diagnose and classify clinically, and the disease develops rapidly. Therefore, the primary tumor detected in patients with CUP plays a profound role in the diagnosis and treatment of patients. The search for the primary tumor of CUP is also one of the indications for 18F-fluoro-2-deoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). Our objective was to evaluate the role of 18F-FDG PET/CT imaging in primary tumor detection and treatment formulation in patients with CUP. Methods: Sixty-two patients with CUP were selected from a database consisting of 18 802 cases in the Jiangsu Cancer Hospital PET/CT center from May 18, 2016 to November 18, 2022. Clinical data and changes in treatment strategies before and after PET/CT were collected. Results: A total of 42 primary tumors (42/62, 67.7%) were identified by PET/CT examination. The tumor staging of patients before conventional PET/CT imaging (such as CT/magnetic resonance imaging [MRI]/US) and after PET/CT did not change in 28 patients (28/62, 45.2%), whereas for 34 patients (34/62, 54.8%), tumor staging changed. Forty-five patients (45/62, 72.6%) had not developed treatment plans before PET/CT examination, but treatment plans were clarified after PET/CT examination. Thirteen patients (13/62, 21.0%) underwent changes in treatments before and after PET/CT examination. Among the 20 patients (20/62, 32.3%) whose primary tumors were not detected, 16 patients (16/20, 80.0%) had no treatment plans before PET/CT and the treatment plans were defined after PET/CT, 3 patients (3/20, 15.0%) changed the treatment plans before and after PET/CT, and 1 patient (1/20, 5.0%) did not change the treatment plan. Conclusions: The 18F-FDG PET/CT plays an important role in the detection and staging of primary tumors in patients with CUP. The PET/CT findings can not only help clinicians develop appropriate treatment plans for patients with CUP but also serve as an effective approach to improve real-life treatment strategies for these patients. [ABSTRACT FROM AUTHOR]

Background: Even in cancer of unknown primary (CUP), which is rare clinical condition, solitary anterosuperior lymph node (LN) along the common hepatic artery (No.8a LN) enlargement diagnosed as metastatic adenocarcinoma has never been reported. Case presentation: A 68-year-old Japanese male, with a history of early gastric cancer that had been completely treated by endoscopic submucosal dissection 26 years ago, was detected a single enlarged nodule along the common hepatic artery, No.8a LN, incidentally by computed tomography performed for monitoring of interstitial pneumonia. Endoscopic ultra-sound-guided fine needle aspiration revealed that this nodule was adenocarcinoma suggestive of metastasis, but other imaging studies, including upper and lower gastrointestinal endoscopy, positron emission tomography, and ultrasonography did not detect any primary cancer. We have finally diagnosed as the LN metastasis of CUP and performed laparoscopic lymphadenectomy for this tumor. The tumor was approximately 5 cm in size, was in close proximity to the pancreas, and involved part of the right gastric artery and vein. LNs in the No.5 and No.8a areas, including this tumor, were dissected laparoscopically, and radical resection was achieved. The patient had no postoperative complication and was discharged on postoperative day 10. Immunohistopathological findings revealed that the tumor was poorly differentiated adenocarcinoma, and different from the histology of gastric cancer resected 26 years ago, although the tumor was suggestive of gastrointestinal origin. Imaging studies performed 2 and 6 months after discharge also did not reveal a primary site. Conclusion: We reported a case of solitary No.8a LN adenocarcinoma of CUP. For diagnostic and therapeutic purposes, radical resection is recommended for single enlarged intra-abdominal LN of CUP. [ABSTRACT FROM AUTHOR]

The current work-up of the primary tumor site of a head and neck squamous cell carcinoma of unknown primary is not standardized and results in several time-consuming procedures that delay treatment initiation. This article seeks to consolidate contemporary strategies used to identify the primary tumor site of an unknown primary head and neck squamous cell carcinoma and offer recommendations based on current literature review. [ABSTRACT FROM AUTHOR]

The Cancer of Unknown Primary (CUP) syndrome is characterized by identifiable metastases while the primary tumor remains hidden. In recent years, various data-driven approaches have been suggested to predict the location of the primary tumor (LOP) in CUP patients promising improved diagnosis and outcome. These LOP prediction approaches use high-dimensional input data like images or genetic data. However, leveraging such data is challenging, resource-intensive and therefore a potential translational barrier. Instead of using high-dimensional data, we analyzed the LOP prediction performance of low-dimensional data from routine medical care. With our findings, we show that such low-dimensional routine clinical information suffices as input data for tree-based LOP prediction models. The best model reached a mean Accuracy of 94% and a mean Matthews correlation coefficient (MCC) score of 0.92 in 10-fold nested cross-validation (NCV) when distinguishing four types of cancer. When considering eight types of cancer, this model achieved a mean Accuracy of 85% and a mean MCC score of 0.81. This is comparable to the performance achieved by approaches using high-dimensional input data. Additionally, the distribution pattern of metastases appears to be important information in predicting the LOP.

Abstract Rationale Cancer of unknown primary (CUP) is a group of rare malignancies with poor prognosis and unidentifiable tissue-of-origin. Distinct DNA methylation patterns in different tissues and cancer types enable the identification of the tissue of origin in CUP patients, which could help risk assessment and guide site-directed therapy. Methods Using genome-wide DNA methylation profile datasets from The Cancer Genome Atlas (TCGA) and machine learning methods, we developed a 200-CpG methylation feature classifier for CUP tissue of origin prediction (MFCUP). MFCUP was further validated with public-available methylation array data of 2977 specimens and targeted methylation sequencing of 78 Formalin‐fixed paraffin‐embedded (FFPE) samples from a single center. Results MFCUP achieved an accuracy of 97.2% in a validation cohort (n = 5923) representing 25 cancer types. When applied to an Infinium 450 K array dataset (n = 1052) and an Infinium EPIC (850 K) array dataset (n = 1925), MFCUP achieved an overall accuracy of 93.4% and 84.8%, respectively. Based on MFCUP, we established a targeted bisulfite sequencing panel and validated it with FFPE sections from 78 patients of 20 cancer types. This methylation sequencing panel correctly identified tissue of origin in 88.5% (69/78) of samples. We also found that the methylation levels of specific CpGs can distinguish one cancer type from others, indicating their potential as biomarkers for cancer diagnosis and screening. Conclusion Our methylation-based cancer classifier and targeted methylation sequencing panel can predict tissue of origin in diverse cancer types with high accuracy.

Objective: Metastatic squamous cell carcinoma (SCC) of inguinal lymph node region with unknown origin is a rare condition. A patient was diagnosed to have vulvar SCC 7 years after the initial diagnosis of inguinal nodal metastatic SCC of unknown primary. Case report: A 59-year-old woman with metastatic SCC of unknown origin in the right inguinal lymph node underwent tumor resection and no evidence of residual disease or possible tumor origin was detected after the surgery and a comprehensive work-up. Seven years later, she was diagnosed to have invasive right vulvar SCC with right pelvic lymph node metastasis. We performed a series of tests to evaluate the relationship between these two events. Conclusion: According to our investigation, the possible relationship between the two events could not be ruled out. This case emphasizes the possibility of late recurrence and the importance of long-term follow up for patients with isolated nodal CUP.

Abstract Background Previous studies on cancer of unknown primary (CUP) mainly focus on treatment and prognosis in western populations and lacked clinical evaluation of different IHC markers, so this study aimed to evaluate characteristics of CUP and recommend a diagnostic strategy from a single center in China. Methods and results Data of 625 patients with CUP were retrospectively collected and reviewed. The patients ranged in age from 20 to 91 years, with a female-to-male ratio of 1.3:1. The predominant histological type was poor or undifferentiated adenocarcinomas (308; 49.3%). The results of Canhelp-Origin molecular testing for the identification of the tissue of origin in 262 of 369 patients (71.0%) were considered predictable (similarity score > 45), with the most common predicted primary tumor site being the breast (57, 21.8%). Unpredictable molecular results correlated with more aggressive clinical parameters and poor survival. Thee positivity rates of several targeted antibodies (GATA3, GCDFP15, TTF1, Napsin A, and PAX8), based on the clinically predicted site, were lower than those reported for the corresponding primary tumors. Nonetheless, TRPS1 and INSM1 were reliable markers of predicted breast carcinoma (75.0%) and neuroendocrine tumors (83.3%), respectively. P16 expression, as well as HPV and EBER testing contributed significantly to the diagnosis of squamous cell carcinomas. Survival analysis revealed that older ages (> 57), ≥ 3 metastatic sites, non-squamous cell carcinomas, bone/liver/lung metastases, unpredictable molecular results, and palliative treatment correlated with poor overall survival. Conclusions We recommend a CUP diagnostic strategy involving the use of targeted antibody panels as per histological findings that is potentially applicable in clinical practice. The markers TRPS1, INSM1, and P16 expression, as well as HPV and EBER testing are particularly valuable in this aspect. Molecular testing is also predictive of survival rates.

Cancer of unknown primary (CUP) is a heterogeneous tumor type that has been diagnosed as a metastatic tumor by pathological examination, but the primary tumor cannot be identified through comprehensive clinical examination. The incidence of CUP accounts for approximately 1%–2% of all tumors. CUP progresses rapidly and has a short course. The treatment and prognosis of patients with CUP are closely linked to the primary site. In clinical settings, identifying the primary tumor remains challenging. Scholars have focused on improving the detection rate. Novel technologies, such as gene expression profiling, high-throughput sequencing, epigenetics, and liquid biopsy, have been successively applied to identify the primary tumor of CUP accurately, sensitively and specifically. With the guidance of molecular diagnosis, targeted therapy, immunotherapy, and combination therapy will usher in the era of precision treatment for CUP, which may become a typical example for individualized therapy.

Abstract Introduction Soft tissue metastasis (STM) of cancers, encompassing skeletal muscle and subcutaneous tissue metastasis, is less common due to unique homeostatic conditions. With longer life expectancy and the advent of new imaging modalities, clinical physicians will increasingly encounter and manage such cases. This study retrospectively reviewed cases of STM in visceral cancers who underwent surgery at Fudan University Shanghai Cancer Center over a 7‐year period. Methods Data were collected through a comprehensive review of medical records, including demographic variables, primary tumor characteristics, surgical data, tumor pathology, and outcomes. Survival analysis was performed using Kaplan–Meier curves. Results The study included 77 cases with a median follow‐up period of 854 days. The most common primary tumor sites were the lung (11) and breast (10). The abdominal wall was the most frequent site of metastasis. The combination of visceral metastasis, age over 52 years, and a history of primary tumor correlates with a poorer prognosis. Surgical‐related metastases are associated with a higher degree of differentiation. Additionally, we have identified a better prognosis for patients with cancer of unknown primary (CUP) exhibiting potential resectable soft tissue metastases. Conclusion The combination of visceral metastasis, age over 52 years, and a history of primary tumor suggest a poorer prognosis. While no significant impact on survival was observed for patients with lymph node metastasis. Surgical‐related metastases are associated with a higher degree of differentiation. CUP patients with potentially resectable soft tissue metastases should be considered for surgical intervention.

In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.

Rationale: Cancer of unknown primary (CUP) is a group of rare malignancies with poor prognosis and unidentifiable tissue-of-origin. Distinct DNA methylation patterns in different tissues and cancer types enable the identification of the tissue of origin in CUP patients, which could help risk assessment and guide site-directed therapy. Methods: Using genome-wide DNA methylation profile datasets from The Cancer Genome Atlas (TCGA) and machine learning methods, we developed a 200-CpG methylation feature classifier for CUP tissue of origin prediction (MFCUP). MFCUP was further validated with public-available methylation array data of 2977 specimens and targeted methylation sequencing of 78 Formalin‐fixed paraffin‐embedded (FFPE) samples from a single center. Results: MFCUP achieved an accuracy of 97.2% in a validation cohort (n = 5923) representing 25 cancer types. When applied to an Infinium 450 K array dataset (n = 1052) and an Infinium EPIC (850 K) array dataset (n = 1925), MFCUP achieved an overall accuracy of 93.4% and 84.8%, respectively. Based on MFCUP, we established a targeted bisulfite sequencing panel and validated it with FFPE sections from 78 patients of 20 cancer types. This methylation sequencing panel correctly identified tissue of origin in 88.5% (69/78) of samples. We also found that the methylation levels of specific CpGs can distinguish one cancer type from others, indicating their potential as biomarkers for cancer diagnosis and screening. Conclusion: Our methylation-based cancer classifier and targeted methylation sequencing panel can predict tissue of origin in diverse cancer types with high accuracy. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) represents a significant diagnostic and therapeutic challenge, being the third to fourth leading cause of cancer death, despite advances in diagnostic tools. This article presents a successful approach using a novel genomic analysis in the evaluation and treatment of a CUP patient, leveraging whole-exome sequencing (WES) and RNA sequencing (RNA-seq). The patient, with a history of multiple primary tumors including urothelial cancer, exhibited a history of rapid progression on empirical chemotherapy. The application of our approach identified a molecular target, characterized the tumor expression profile and the tumor microenvironment, and analyzed the origin of the tumor, leading to a tailored treatment. This resulted in a substantial radiological response across all metastatic sites and the predicted primary site of the tumor. We argue that a comprehensive genomic and molecular profiling approach, like the BostonGene© Tumor Portrait, can provide a more definitive, personalized treatment strategy, overcoming the limitations of current predictive assays. This approach offers a potential solution to an unmet clinical need for a standardized approach in identifying the tumor origin for the effective management of CUP. [ABSTRACT FROM AUTHOR]

Background: Biomarkers of systemic inflammation have been shown to predict outcomes in patients with cancer of unknown primary (CUP). We sought to validate these findings in patients with confirmed CUP (cCUP) and explore their role alongside existing clinicopathological prognostic categories. Patients and Methods: CUP oncologist from across the United Kingdom were invited to include patients with cCUP referred to their local CUP multidisciplinary team. Patient demographics, clinical, pathological and outcome data were recorded and analysed. Results: Data were available for 548 patients from four CUP services. 23% (n = 124) of patients met clinicopathological criteria for favourable‐risk cCUP. On multivariate analysis c‐reactive protein (CRP) (p < 0.001) and the Scottish Inflammatory Prognostic Score (SIPS: combining albumin and neutrophil count) (p < 0.001) were independently predictive of survival. CRP and SIPS effectively stratified survival in patients with both favourable‐risk and poor‐risk cCUP based on clinicopathological features. Conclusions: Biomarkers of systemic inflammation are reliable prognostic factors in patients with cCUP, regardless of clinicopathological subgroup. We recommend that CRP or SIPS are incorporated into routine clinical assessments of patients with cCUP as a tool to aid investigation and/or treatment decision‐making across all groups. Established clinicopathological factors can then be used to inform management pathways and specific systemic anticancer therapy selection. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) presents a complex diagnostic challenge, characterized by metastatic tumors of unknown tissue origin and a dismal prognosis. This review delves into the emerging significance of artificial intelligence (AI) and machine learning (ML) in transforming the landscape of CUP diagnosis, classification, and treatment. ML approaches, trained on extensive molecular profiling data, have shown promise in accurately predicting tissue of origin. Genomic profiling, encompassing driver mutations and copy number variations, plays a pivotal role in CUP diagnosis by providing insights into tumor type-specific oncogenic alterations. Mutational signatures (MS), reflecting somatic mutation patterns, offer further insights into CUP diagnosis. Known MS with established etiology, such as ultraviolet (UV) light-induced DNA damage and tobacco exposure, have been identified in cases of dedifferentiated/transdifferentiated melanoma and carcinoma. Deep learning models that integrate gene expression data and DNA methylation patterns offer insights into tissue lineage and tumor classification. In digital pathology, machine learning algorithms analyze whole-slide images to aid in CUP classification. Finally, precision oncology, guided by molecular profiling, offers targeted therapies independent of primary tissue identification. Clinical trials assigning CUP patients to molecularly guided therapies, including targetable alterations and tumor mutation burden as an immunotherapy biomarker, have resulted in improved overall survival in a subset of patients. In conclusion, AI- and ML-driven approaches are revolutionizing CUP management by enhancing diagnostic accuracy. Precision oncology utilizing enhanced molecular profiling facilitates the identification of targeted therapies that transcend the need to identify the tissue of origin, ultimately improving patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Cancer of unknown primary (CUP) is a challenging malignancy. The purpose of this study was to investigate the clinical characteristics and prognosis of bone metastatic CUP using the population-based Surveillance, Epidemiology, and End Results (SEER) database. Methods: From the SEER database, we identified 1908 patients with bone metastatic CUP at initial presentation between 2010 and 2018. Histology was subdivided following International Classification of Diseases for Oncology codes as Adenocarcinoma, Squamous cell, Neuroendocrine, or Carcinoma not otherwise specified (NOS). Cox proportional hazard modeling was applied using factors of age, sex, ethnicity, histological subtype, and therapeutic intervention. Results: Among the 1908 patients, histology was Neuroendocrine in 240 patients, Squamous cell in 201 patients, Adenocarcinoma in 810 patients and NOS in 657 patients. In each subtype, patients tended to be predominantly male and white. Chemotherapy was introduced for 28% of patients and radiation for 34% in the entire cohort. Survival in patients with bone metastatic CUP was unfavorable, with a median survival of 2 months. Among the histological subtypes, Adenocarcinoma showed shorter survival than the other groups. In addition, treatment interventions such as chemotherapy and radiation therapy prolonged survival, particularly for Squamous cell, Adenocarcinoma and NOS, but not for Neuroendocrine. Discussion: Bone metastatic CUP showed extremely poor prognosis, but treatment interventions such as chemotherapy and radiation generally offered survival benefits. Further randomized clinical research is needed to confirm the present results. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective and prospective cohort study. Objectives: Survival estimation is necessary in the decision-making process for treatment in patients with spinal metastasis from cancer of unknown primary (SMCUP). We aimed to develop a novel survival prediction system and compare its accuracy with that of existing survival models. Methods: A retrospective derivation cohort of 268 patients and a prospective validation cohort of 105 patients with SMCUP were performed. Univariate and multivariable survival analysis were used to generate independently prognostic variables. A nomogram model for survival prediction was established by integrating these independent predictors based on the size of the significant variables' β regression coefficient. Then, the model was subjected to bootstrap validation with calibration curves and concordance index (C-index). Finally, predictive accuracy was compared with Tomita, revised Tokuhashi and SORG score by the receiver-operating characteristic (ROC) curve. Results: The survival prediction model included six independent prognostic factors, including pathology (P <.001), visceral metastases (P <.001), Frankel score (P <.001), weight loss (P =.005), hemoglobin (P =.001) and serum tumor markers (P <.001). Calibration curve of the model showed good agreement between predicted and actual mortality risk in 6-, 12-, and 24-month estimation in derivation and validation cohorts. The C-index was.775 in the derivation cohort and.771 in the validation cohort. ROC curve analysis showed that the current model had the best accuracy for SMCUP survival estimation amongst 4 models. Conclusions: The novel nomogram system can be applied in survival prediction for SMCUP patients, and furtherly be used to give individualized therapeutic suggestions based on patients' prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Soft tissue metastasis (STM) of cancers, encompassing skeletal muscle and subcutaneous tissue metastasis, is less common due to unique homeostatic conditions. With longer life expectancy and the advent of new imaging modalities, clinical physicians will increasingly encounter and manage such cases. This study retrospectively reviewed cases of STM in visceral cancers who underwent surgery at Fudan University Shanghai Cancer Center over a 7‐year period. Methods: Data were collected through a comprehensive review of medical records, including demographic variables, primary tumor characteristics, surgical data, tumor pathology, and outcomes. Survival analysis was performed using Kaplan–Meier curves. Results: The study included 77 cases with a median follow‐up period of 854 days. The most common primary tumor sites were the lung (11) and breast (10). The abdominal wall was the most frequent site of metastasis. The combination of visceral metastasis, age over 52 years, and a history of primary tumor correlates with a poorer prognosis. Surgical‐related metastases are associated with a higher degree of differentiation. Additionally, we have identified a better prognosis for patients with cancer of unknown primary (CUP) exhibiting potential resectable soft tissue metastases. Conclusion: The combination of visceral metastasis, age over 52 years, and a history of primary tumor suggest a poorer prognosis. While no significant impact on survival was observed for patients with lymph node metastasis. Surgical‐related metastases are associated with a higher degree of differentiation. CUP patients with potentially resectable soft tissue metastases should be considered for surgical intervention. [ABSTRACT FROM AUTHOR]

Background: Previous studies on cancer of unknown primary (CUP) mainly focus on treatment and prognosis in western populations and lacked clinical evaluation of different IHC markers, so this study aimed to evaluate characteristics of CUP and recommend a diagnostic strategy from a single center in China. Methods and results: Data of 625 patients with CUP were retrospectively collected and reviewed. The patients ranged in age from 20 to 91 years, with a female-to-male ratio of 1.3:1. The predominant histological type was poor or undifferentiated adenocarcinomas (308; 49.3%). The results of Canhelp-Origin molecular testing for the identification of the tissue of origin in 262 of 369 patients (71.0%) were considered predictable (similarity score > 45), with the most common predicted primary tumor site being the breast (57, 21.8%). Unpredictable molecular results correlated with more aggressive clinical parameters and poor survival. Thee positivity rates of several targeted antibodies (GATA3, GCDFP15, TTF1, Napsin A, and PAX8), based on the clinically predicted site, were lower than those reported for the corresponding primary tumors. Nonetheless, TRPS1 and INSM1 were reliable markers of predicted breast carcinoma (75.0%) and neuroendocrine tumors (83.3%), respectively. P16 expression, as well as HPV and EBER testing contributed significantly to the diagnosis of squamous cell carcinomas. Survival analysis revealed that older ages (> 57), ≥ 3 metastatic sites, non-squamous cell carcinomas, bone/liver/lung metastases, unpredictable molecular results, and palliative treatment correlated with poor overall survival. Conclusions: We recommend a CUP diagnostic strategy involving the use of targeted antibody panels as per histological findings that is potentially applicable in clinical practice. The markers TRPS1, INSM1, and P16 expression, as well as HPV and EBER testing are particularly valuable in this aspect. Molecular testing is also predictive of survival rates. [ABSTRACT FROM AUTHOR]

Introduction: The following study aimed to answer the question if HPV-HNCUP and HPV-OPSCC are the same disease. Propensity score matching (PSM) was used to compare the oncological outcomes of both groups, in particular the 5-year overall survival rate (OS), the 5-year disease specific survival rate (DSS) and the 5-year progression free survival rate (PFS). Materials and methods: Firstly, between January 1st, 2007, and March 31st, 2020 a total of 131 patients were treated with HNCUP at our Department. Out of these, 21 patients with a confirmed positive p16 status were referred to surgery followed by adjuvant therapy. Secondly, between January 1st, 2000, and January 31st, 2017, a total of 1596 patients were treated with an OPSSC at our Department. Out of these, 126 patients with a confirmed positive p16 status were referred to surgery followed by adjuvant therapy. After PSM, 84 patients with HPV-OPSCC and 21 HPV-HNCUP remained in the study for further comparison. Results: The OS was 63.5% (95% CI 39.4–87.6) for HPV-HNCUP and 88.9% (95% CI 90.4–100.0) for HPV-OPSCC patients and therefore, significantly lower for the first mentioned (p = 0.013). The DSS was also significantly impaired for HPV-HNCUP (71.0%, 95% CI 46.3–95.7), in comparison with HPV-OPSCC patients (95.5%, 95% CI 90.4–100.0; p = 0.002). The PFS for HPV-HNCUP patients was lower (75.6%, 95% CI 54.0–97.2) yet not significantly different to HPV-OPSCC (90.4%, 95% CI 83.5–97.3; p = 0.067). Conclusions: The results presented demonstrate a significant reduced OS and DSS for HPV-HNCUP patients. Accordingly, in our study HPV-HNCUP and HPV-OPSCC are two different entities with a different oncological outcome. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) is a heterogeneous tumor type that has been diagnosed as a metastatic tumor by pathological examination, but the primary tumor cannot be identified through comprehensive clinical examination. The incidence of CUP accounts for approximately 1%–2% of all tumors. CUP progresses rapidly and has a short course. The treatment and prognosis of patients with CUP are closely linked to the primary site. In clinical settings, identifying the primary tumor remains challenging. Scholars have focused on improving the detection rate. Novel technologies, such as gene expression profiling, high- throughput sequencing, epigenetics, and liquid biopsy, have been successively applied to identify the primary tumor of CUP accurately, sensitively and specifically. With the guidance of molecular diagnosis, targeted therapy, immunotherapy, and combination therapy will usher in the era of precision treatment for CUP, which may become a typical example for individualized therapy. [ABSTRACT FROM AUTHOR]

Purpose: Cancer of unknown primary (CUP) accounts for 2–5% of all cancer diagnoses, wherein standard investigations fail to reveal the original tumor site. Basket trials allocate targeted therapeutics based on actionable somatic mutations, independent of tumor entity. These trials, however, mostly rely on variants identified in tissue biopsies. Since liquid biopsies (LB) represent the overall tumor genomic landscape, they may provide an ideal diagnostic source in CUP patients. To identify the most informative liquid biopsy compartment, we compared the utility of genomic variant analysis for therapy stratification in two LB compartments (circulating cell-free (cf) and extracellular vesicle (ev) DNA). Methods: CfDNA and evDNA from 23 CUP patients were analyzed using a targeted gene panel covering 151 genes. Identified genetic variants were interpreted regarding diagnostic and therapeutic relevance using the MetaKB knowledgebase. Results: LB revealed a total of 22 somatic mutations in evDNA and/or cfDNA in 11/23 patients. Out of the 22 identified somatic variants, 14 are classified as Tier I druggable somatic variants. Comparison of variants identified in evDNA and cfDNA revealed an overlap of 58% of somatic variants in both LB compartments, whereas over 40% of variants were only found in one or the other compartment. Conclusion: We observed substantial overlap between somatic variants identified in evDNA and cfDNA of CUP patients. Nonetheless, interrogation of both LB compartments can potentially increase the rate of druggable alterations, stressing the significance of liquid biopsies for possible primary-independent basket and umbrella trial inclusion. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) is a metastatic syndrome with an unidentifiable primary tumor even after comprehensive clinical and pathological investigations, accounting for approximately 2%-5% of all newly diagnosed cancers. CUP has some common features including aggressiveness, early dissemination and poor prognosis. With the application of novel molecular tests and drugs, the diagnostic value of gene expression assay and genomic tests in characterizing the molecular features has become increasingly prominent, and new treatment options such as molecular-guided targeted therapy and immunotherapy have become available. This article reviewed the clinical trials of CUP reported at 2023 European Society for Medical Oncology (ESMO) Congress.

Abstract Background Prostate cancer has been well known to have a high prevalence among middle-aged and older men, with high incidence of metastases to the bone—the main metastatic site. However, prostate cancer among those less than 50 years of age is extremely rare, and neck swelling is seldom the initial symptom. Case presentation We herein report case of a 47-year-old Japanese male with poorly differentiated prostate cancer that had been initially diagnosed as a cancer of unknown primary with multiple lymph node and bone metastases before reaching a definitive diagnosis. The patient has been started on endocrine therapy and is currently alive without progression. Discussion and conclusion When locating the primary lesion in men with cancer of unknown primary, it is important to consider the possibility of prostate cancer, confirm serum prostate-specific antigen levels, and perform local prostate evaluation.

Abstract Background Biomarkers of systemic inflammation have been shown to predict outcomes in patients with cancer of unknown primary (CUP). We sought to validate these findings in patients with confirmed CUP (cCUP) and explore their role alongside existing clinicopathological prognostic categories. Patients and Methods CUP oncologist from across the United Kingdom were invited to include patients with cCUP referred to their local CUP multidisciplinary team. Patient demographics, clinical, pathological and outcome data were recorded and analysed. Results Data were available for 548 patients from four CUP services. 23% (n = 124) of patients met clinicopathological criteria for favourable‐risk cCUP. On multivariate analysis c‐reactive protein (CRP) (p

Cancer of unknown primary (CUP) represents a significant diagnostic and therapeutic challenge, being the third to fourth leading cause of cancer death, despite advances in diagnostic tools. This article presents a successful approach using a novel genomic analysis in the evaluation and treatment of a CUP patient, leveraging whole-exome sequencing (WES) and RNA sequencing (RNA-seq). The patient, with a history of multiple primary tumors including urothelial cancer, exhibited a history of rapid progression on empirical chemotherapy. The application of our approach identified a molecular target, characterized the tumor expression profile and the tumor microenvironment, and analyzed the origin of the tumor, leading to a tailored treatment. This resulted in a substantial radiological response across all metastatic sites and the predicted primary site of the tumor. We argue that a comprehensive genomic and molecular profiling approach, like the BostonGene© Tumor Portrait, can provide a more definitive, personalized treatment strategy, overcoming the limitations of current predictive assays. This approach offers a potential solution to an unmet clinical need for a standardized approach in identifying the tumor origin for the effective management of CUP.

Cancer of unknown primary (CUP) is a metastatic syndrome with an unidentifiable primary tumor even after comprehensive clinical and pathological investigations, accounting for approximately 2%-5% of all newly diagnosed cancers. CUP has some common features including aggressiveness, early dissemination and poor prognosis. With the application of novel molecular tests and drugs, the diagnostic value of gene expression assay and genomic tests in characterizing the molecular features has become increasingly prominent, and new treatment options such as molecular-guided targeted therapy and immunotherapy have become available. This article reviewed the clinical trials of CUP reported at 2023 European Society for Medical Oncology (ESMO) Congress. [ABSTRACT FROM AUTHOR]

Background/aim: Cancer of unknown primary (CUP) is a difficult clinical entity to manage. The aim of the study was to investigate the sociodemographic and pathological characteristics, treatment options, and factors affecting overall survival (OS) in CUP patients whose primary tumor was not detected during follow-up. Materials and methods: A total of 243 CUP patients whose primary tumors could not be detected during follow-up were included in the study. Their demographic characteristics, survival outcomes, and prognostic factors were investigated. Results: Of the 243 patients included in this study, 61.7% were male and 38.3% were female, and the median age was 61 (range: 19-90) years. The most common histological type was adenocarcinoma (79%). The median follow-up time of the patients was 30.3 months (95% CI: 11.4-49.3), the median OS time was 9.1 months (95% CI: 7.2-11.0), and 72.4% of the patients received at least 1 line of chemotherapy (CT). The difference in survival between the patients who did and did not receive CT was statistically significant (median OS: 10.1 vs. 4.2 months, p = 0.003). According to the multivariate analysis, the presence of cholestasis (HR: 0.48, 95% CI: 0.29-0.79, p = 0.004), lung metastasis (HR: 0.69, 95% CI: 0.51-0.95, p = 0.001), second-line chemotherapy (HR: 1.69, 95% CI: 1.14-2.49, p < 0.001), and Eastern Cooperative Oncology Group (ECOG) performance status (HR: 0.20, 95% CI: 0.10-0.40, p < 0.001) were independent prognostic factors influencing OS. Conclusion: CUP patients who receive multiple lines of chemotherapy tend to have longer survival. This is the first study to report cholestasis as a prognostic factor in CUP patients. In addition, the presence of lung metastases, not receiving second-line chemotherapy, and ECOG performance status (=2) were found to be independent poor prognostic factors. [ABSTRACT FROM AUTHOR]

Patients with head and neck squamous cell carcinoma of unknown primary (HNCUP) are often treated with extensive radiotherapy (RT). Frequently, the bilateral nodal clinical target volume (nCTV) and the volumes of suspected mucosal primary sites (mCTV) of the pharynx and larynx is irradiated. This treatment is effective but toxic. New data suggest that omission of the contralateral nCTV and mCTV, results in few recurrences. The present study explores photon versus proton therapy, in the primary and recurrent setting. An analysis of twelve patients previously treated for HNCUP was performed. A fictitious recurrence was defined in patients treated for unilateral disease. Independently a volumetric arc photon plan and an intensity-modulated proton plan was made for all cases and scenarios. Compared to the standard bilateral treatment this study shows that limiting the target to unilateral nCTV leads to a significant decrease in dysphagia of 18% and 17% and xerostomia of 4.0% and 5% for photon and protons, respectively. Comparing photon RT directly to proton RT shows a small and often insignificant gain, using protons for both bilateral and unilateral targets. Focusing on re-irradiation, benefits from using protons in both the primary setting and at re-irradiation were limited. However, using protons for re-irradiation only leads to a decrease in the tissue volume receiving a specific dose outside the target overlapping region, e.g., V90Gymean was 31, 25, and 22 cm3 for photons-photons, photons-protons, and protons-protons, respectively. For V100Gy of the ipsilateral carotid artery, no differences were observed. Omitting contralateral nCTV irradiation and mCTV irradiation will significantly reduce toxicity. The accumulated high dose volumes can be minimised using protons for re-irradiation. However, the use of protons for primary treatment provides limited benefit in most patients. [ABSTRACT FROM AUTHOR]

Cancers of unknown primary (CUP) account for 2%-5% of all diagnosed cancers and are always characterized with fast-paced aggression, early metastasis, and unpredictable spread patterns Mediastinum metastasis with unknown primary origin is extremely rare and with a poor prognosis and short survival. There is no literature to refer to for its treatment. Here, we reported a case of squamous cell CUP in the mediastinum. A 50-year-old male patient was admitted after multiline treatment of low differentiated squamous cell carcinoma in the mediastinum diagnosed 8 months before. In August 2019, the patient went to a local hospital for cough and dyspnea for 2 weeks. Then, he was diagnosed with squamous cell carcinoma of unknown primary origin with multiple lymph nodes metastasis. The patient was featured with programmed cell death-ligand 1 (PD-L1) expression strongly positive in 90% of tumor cells and the combined positive score of 90 and a tumor mutation burden of 1.79 MUts/Mb and microsatellite stable phenotype. The patient was treated with anti-programmed cell death-1 (PD-1) antibodies in combination with chemotherapy and responded to the treatment. The patient showed stable disease to multi-line immunotherapy for more than 7 months and finally got a clinical benefit of 2-year survival benefit. In conclusion, immunotherapy targeting PD-1/PD-L1 in combination with chemotherapy may play a crucial role in the later-line treatment and palliative care of CUP. [ABSTRACT FROM AUTHOR]

Management of patients with head and neck cancer of unknown primary (HNCUP) is challenging. To provide a long-term analysis focusing on protective survival factors for clinical decision-making. Furthermore, the prognostic value of the current N classification system was evaluated. We retrospectively analyzed patients with HNCUP between 2003 and 2016. Univariate and multivariate analyses were used to investigate predictors of overall survival (OS). A primary tumor was found in 67 of 290 patients with suspected HNCUP, leaving after exclusion 141 HNCUP cases for analysis, who received multi-step therapy (MST) (n = 108) or single therapy (n = 28). Chemotherapy (CT) (n = 101), curative MST, ≤3 positive lymph nodes (LN) (n = 33), squamous cell carcinoma (SCC) (n = 123), HPV+ (n = 21), M0 (n = 70) increased OS by 21.8%, 24.4%, 12.7%, 6.8%, 18.7%, 29.6%, respectively. 5- and 10-year OS was 78.1%/66.6%. The number of metastatic LNs predicted OS is better than N classification. Aspects for clinical decision-making: Curative MST and SCC histology were the most significant predictors for improved OS. Categorizing LN into 1, 2-3, and >3 LNs was more significant than the traditional N classification. The addition of CT to curative MST has a stronger impact on survival than HPV and N classifications. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer has been well known to have a high prevalence among middle-aged and older men, with high incidence of metastases to the bone—the main metastatic site. However, prostate cancer among those less than 50 years of age is extremely rare, and neck swelling is seldom the initial symptom. Case presentation: We herein report case of a 47-year-old Japanese male with poorly differentiated prostate cancer that had been initially diagnosed as a cancer of unknown primary with multiple lymph node and bone metastases before reaching a definitive diagnosis. The patient has been started on endocrine therapy and is currently alive without progression. Discussion and conclusion: When locating the primary lesion in men with cancer of unknown primary, it is important to consider the possibility of prostate cancer, confirm serum prostate-specific antigen levels, and perform local prostate evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine neoplasms (NENs) of unknown primary (NEN-UPs) encompass a small group within all diagnosed NENs. As a result, diagnostic work-up and the therapy algorithm are not standardized. In this study we consecutively analyzed a cohort of 113 patients, initially diagnosed as NEN-UPs. After extensive diagnostic work-up, in 11.5% (13 patients) a primary tumor site could be identified. Our study revealed that an extensive diagnostic work-up, in particular somatostatin receptor (SSTR)-PET, is associated with a better clinical outcome. Our study proposes that a detailed diagnostic investigation and the identification of a primary tumor site can provide the rationale for a tumor-specific therapy, contributing to a prolonged survival in NEN-UPs. Neuroendocrine neoplasms (NENs) represent a rare and heterogenous group of tumors with predominantly gastroenteropancreatic or pulmonary origin. Despite numerous diagnostic efforts, the primary tumor site remains unknown in up to 20% of the patients diagnosed with NEN. In this subgroup of NEN patients, a standard diagnostic algorithm has not yet been integrated into clinical routine. Of note, an undetermined primary tumor site in NENs is associated with an impaired clinical outcome by at least "formally" limiting treatment options exclusively approved for NENs of a certain histological origin. In this retrospective study, a patient cohort of 113 patients initially diagnosed with NEN of unknown primary (NEN-UP) was analyzed. In 13 patients (11.5%) a primary tumor site could be identified subsequently, amongst others, by performing somatostatin receptor (SSTR)-PET-based imaging, which was irrespective of the initial clinical or demographic features. Diagnostic work-up and therapeutic regimens did not differ significantly between patients with an identified or unidentified primary tumor site; only a detailed immunohistochemical assessment providing additional information on the tumor origin proved to be significantly associated with the detection of a primary tumor site. Our study revealed that a profound diagnostic work-up, particularly including SSTR-PET-based imaging, leads to additional treatment options, finally resulting in significantly improved clinical outcomes for patients with NEN-UPs. [ABSTRACT FROM AUTHOR]

Purpose: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. Methods: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. Results: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). Conclusion: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients. [ABSTRACT FROM AUTHOR]

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