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Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and fluorescence in situ hybridization analysis identified FGFR2 gene amplification in both models, in the form of homogeneously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation., Competing Interests: Declaration of interests F.G. received personal fees from AstraZeneca and honoraria for advisory board participation from Eli-Lilly. G.A.C. is a member of the Editorial Board of Molecular Therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-naïve CUP patients., Methods: Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines., Results: Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1-positive CUP (TPS ≥1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0-18.0; HR 0.3, p < 0.001). The benefit of PD-L1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0-37.0 versus 10 months, 95 %CI 3.1-16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS ≥50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4)., Conclusion: PD-L1 expression associates with favorable survival in checkpoint inhibitor-naïve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recently, organ preservation has gained importance for head and neck malignancies. The negative consequences of the therapies can be reduced without compromising the survival and the quality of life. Accordingly, transoral robotic surgery (TORS) is gaining ground internationally. We have been performing TORS procedures at the University of Pécs since January 2023. We operated on 27 patients until July 2024, including fifteen p16-positive tumors. Neck dissections were performed in 19 cases. The use of TORS is helpful in oropharyngeal cases, where inaccessible structures can be reached minimally invasively, compared to other transoral approaches. This is important for young patients with human papillomavirus-associated tumors, which have a better prognosis and longer life expectancy. TORS also has advantages over the previously used approaches for cancer of unknown primary (CUP). Compared to the standardly used FDG-PET/CT and "blindly" taken biopsies, TORS offers a higher detection rate of the primary tumor, by performing tonsillectomy and complete mucosectomy of the tongue base.

BACKGROUND Occult breast cancer (OBC) is diagnosed when regional or distant metastases are found without evidence of a primary tumor. The low overall incidence is a great challenge for the management strategy of OBC. Aggressive diagnosis and personalized treatment are feasible treatment strategies for OBC. We report the case of an OBC patient who achieved pathological complete response (pCR) after neoadjuvant chemotherapy. CASE REPORT A 43-year-old woman was admitted to the hospital 6 months after detecting a lump in her left axilla, about the size of a quail egg, but not red or swollen, and the lump gradually grew. Mammography, ultrasound, and magnetic resonance imaging showed a visible left axilla lesion but no nodules in bilateral breasts. A core-needle biopsy of the axilla lesion revealed an invasive carcinoma of breast origin. The tumor cells were estrogen receptors (ER)-negative, progesterone receptor (PR)-negative, and HER2-positive (3+) by immunohistochemistry. The patient was finally diagnosed with HER2-positive, hormone receptor-negative occult breast cancer of the left breast, cT0N2M0, stage IIIA. The TCbHP regimen (docetaxel, carboplatin, trastuzumab, and pertuzumab) as neoadjuvant chemotherapy was given. She underwent a modified radical mastectomy, showing a pCR. Subsequent radiotherapy and HER2-targeted therapy were administrated. CONCLUSIONS This case highlights that even aggressive HER2-positive breast cancer can present as an occult primary tumor. Our clinical experience suggests that neoadjuvant chemotherapy followed by modified radical mastectomy can be effective for treating such rare cases. The patient achieved pCR, which can provide a therapeutic strategy for effective treatment of similar OBCs.

Introduction: This systematic review aims to evaluate the role of biopsies in non-oropharyngeal subsites in patients with cervical metastasis from head and neck squamous cell carcinoma of unknown primary (HNSCCUP)., Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Articles that encompassed non-oropharyngeal biopsies in HNSCCUP as part of the diagnostic work-up were selected and analysed., Results: A comprehensive search strategy was used to search relevant literature in PubMed from inception to October 2021. Eleven articles out of 860 were included, comprising 990 patients. There are no randomised control trials comparing the outcomes of survival and or locoregional control between patients who have or have not undergone non-targeted biopsies of non-oropharyngeal sub-sites for HNSCCUP. Several retrospective studies which showed an extremely low yield from random biopsies (range of yield, 0%-9%) of non-oropharyngeal subsites. Even targeted biopsies showed a low yield (range of yield, 0.6%-16.6%) from non-oropharyngeal subsites. The primary site identified for Epstein-Barr virus (EBV) positive cervical lymph nodes with an unknown primary is mainly the nasopharynx (51.7%). Narrow band imaging (NBI) (sensitivity range, 64%-91%) helps in the detection of primaries to target biopsies in non-oropharyngeal subsites., Conclusions: On the basis of this systematic review, it is not appropriate to offer biopsies of clinically and radiologically normal upper aerodigestive tract mucosa at non-oropharyngeal sites. Offer nasopharyngeal biopsies when the cervical node sampling reveals EBV-positive metastasis. Where available, NBI should be used to help detect and target biopsies in non-oropharyngeal subsites., (© 2024 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Background: Head and neck carcinoma of unknown primary (CUP) represents a challenging diagnostic process when standard work-up fails to identify the primary tumour site. The aim of this systematic review and meta-analysis was to evaluate the diagnostic utility and complication profile of transoral robotic surgery (TORS) tongue base mucosectomy (TBM) in the management of CUP., Patients and Methods: An electronic database search was performed in the EMBASE, MEDLINE, PubMed and Cochrane databases. A meta-analysis of proportions was performed to obtain an estimate of the overall proportion for the detection and complication rates., Results: Nine studies representing 235 patients with CUP who had TORS TBM were included in the final analysis. The overall pooled tumour detection rate was 66.2% [95% confidence interval (CI) 56.1-75.8]. The incidence of tumour detection in human papilloma virus (HPV)-positive cases (81.5%, 95% CI 60.8-96.4) was significantly higher than HPV-negative cases (2.3%, 95% CI 0.00-45.7). Weighted overall complication rate was 11.4% (95% CI 7.2-16.2). The majority were grade I or II (80%) according to the Clavien-Dindo classification., Conclusions: This meta-analysis suggests TORS to be safe and effective in localising the primary tumour site in patients with CUP. While the current data supports the use of TORS in patients who are HPV positive, larger numbers of HPV-negative cases are required to determine the true diagnostic effect with TORS before any valid conclusions can be inferred in this particular subgroup. Further research should focus on high quality prospective trials with stringent methodological work-up to minimise heterogeneity and allow for more accurate statistical analysis., (© 2024. Society of Surgical Oncology.)

Cancer of unknown primary (CUP) is a rare type of metastatic cancer in which the origin of the tumor is unknown. Since the treatment strategy for patients with metastatic tumors depends on knowing the primary site, accurate identification of the origin site is important. Here, we developed an image-based deep-learning model that utilizes a vision transformer algorithm for predicting the origin of CUP. Using DNA methylation dataset of 8,233 primary tumors from The Cancer Genome Atlas (TCGA), we categorized 29 cancer types into 18 organ classes and extracted 2,312 differentially methylated CpG sites (DMCs) from non-squamous cancer group and 420 DMCs from squamous cell cancer group. Using these DMCs, we created organ-specific DNA methylation images and used them for model training and testing. Model performance was evaluated using 394 metastatic cancer samples from TCGA (TCGA-meta) and 995 samples (693 primary and 302 metastatic cancers) obtained from 20 independent external studies. We identified that the DNA methylation image reveals a distinct pattern based on the origin of cancer. Our model achieved an overall accuracy of 96.95 % in the TCGA-meta dataset. In the external validation datasets, our classifier achieved overall accuracies of 96.39 % and 94.37 % in primary and metastatic tumors, respectively. Especially, the overall accuracies for both primary and metastatic samples of non-squamous cell cancer were exceptionally high, with 96.79 % and 96.85 %, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

During routine dermatologic examination, a 77-year-old male was noted to have a firm blue subcutaneous nodule on his right lateral upper back. His past medical history included metastatic melanoma of unknown primary involving right and left axillary lymph nodes, treated with ipilimumab/nivolumab with complete response, and subsequent primary uveal melanoma. The subcutaneous nodule was located near his previous right axillary scar for metastatic melanoma. Excision of the nodule showed a plexiform neoplasm involving mid and deep dermis composed of spindle and epithelioid atypical cells admixed with numerous melanophages. Central necrosis was present. Immunohistochemical studies revealed the tumor cells to be diffusely positive for HMB45, with retained expression of BAP1 and p16. The tumor cells were negative for PRAME, nuclear expression of β-catenin, LEF1, and BRAF V600E. Molecular studies demonstrated BAP1 and GNA11 somatic mutations, a profile different from that exhibited by his prior melanoma. Collectively, these data were interpreted as a metastasis from uveal melanoma and not a recurrence of his metastatic likely cutaneous melanoma after complete response to immunotherapy. This case emphasizes the importance of molecular studies for definitive diagnosis in challenging clinical situations, especially when there is discordance among histopathological, immunohistochemical, and molecular studies. Integration of clinical, histopathological, and molecular features is warranted., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Patients presenting with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remain challenging clinical scenarios as large variation exists in practices used to locate the primary., Objective: The objective of this systematic review is to review of the literature and offer recommendations for oropharyngeal biopsies in HNSCCUP., Method: Pubmed, Medline and Embase were searched to identify studies from inception to October 2021. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed., Results: A total of 483 articles were included and screened, 41 studies met the inclusion criteria, including over 3400 patients from the original articles (122 of these patients were reported on in two sequential articles by a single author - table 1) and 4 large metaanalyses including 1852 patients. The primary site identification rate following random biopsies or deep tissue biopsies is less than 5% in most studies. The mean detection rate following ipsilateral tonsillectomy is 34%; two pooled analyses indicate that the mean detection rate following tongue base mucosectomy is 64%, with this figure rising when the tonsils are negative., Conclusions: High level evidence is lacking, with heterogeneity in the reported studies. Published meta-analyses are based on retrospective data. There is little evidence supporting the practice of random/non-directed oropharyngeal biopsies. Available evidence supports palatine tonsillectomy and tongue base mucosectomy compared to deep tissue biopsies., (© 2024 John Wiley & Sons Ltd.)

Introduction: To investigate factors influencing survival in head and neck squamous cell carcinoma of unknown primary (HNSCCUP)., Methods: A retrospective observational cohort study was conducted, over 5 years from January 2015, in UK Head and Neck centres, of consecutive adults undergoing 18F-Fluorodeoxyglucose-PET-CT within 3 months of diagnosis with metastatic cervical squamous cell carcinoma. Patients treated as HNSCCUP underwent survival analysis, stratified by neck dissection and/or radiotherapy to the ipsilateral neck, and by HPV status., Results: Data were received from 57 centres for 965 patients, of whom 482 started treatment for HNSCCUP (65.7% HPV-positive, n = 282/429). Five-year overall survival (OS) for HPV-positive patients was 85.0% (95% CI 78.4-92.3) and 43.5% (95% CI 32.9-57.5) for HPV-negative. HPV-negative status was associated with worse OS, disease-free (DFS), and disease-specific (DSS) survival (all p < .0001 on log-rank test) but not local control (LC) (p = .16). Unilateral HPV-positive disease treated with surgery alone was associated with significantly worse DFS (p < .0001) and LC (p < .0001) compared to radiotherapy alone or combined modalities (5-year DFS: 24.9%, 82.3% and 94.3%; 5-year LC: 41.8%, 98.8% and 98.6%). OS was not significantly different (p = .16). Unilateral HPV-negative disease treated with surgery alone was associated with significantly worse LC (p = .017) (5-year LC: estimate unavailable, 93.3% and 96.6%, respectively). Small numbers with bilateral disease precluded meaningful sub-group analysis., Conclusions: HPV status is associated with variable management and outcomes in HNSCCUP. Unilateral neck disease is treated variably and associated with poorer outcomes when managed with surgery alone. The impact of diagnostic oropharyngeal surgery on primary site emergence, survival and functional outcomes is unestablished., (© 2024 John Wiley & Sons Ltd.)

Importance: Current guidelines recommend intraoperative frozen section(s) during diagnostic surgery for squamous cell carcinoma for unknown primary tumors (SCCUP)., Objective: To determine the utility of intraoperative pathology consultation during transoral robotic surgery (TORS) in localizing primary tumors and influencing need for adjuvant therapy., Design, Setting, and Participants: A retrospective case series including 47 adult patients with human papillomavirus (HPV)-associated SCCUP who underwent TORS/oropharyngectomy between January 2016 and February 2023 was carried out at a single tertiary care hospital. The analysis took place on May 13, 2024., Exposures: Nodal stage, tonsillectomy history, extranodal extension (ENE)., Main Outcomes and Measures: Intraoperative pathology consultation and final pathology results were compared with surgical outcomes, including margin revision, need for second procedure and/or radiation with or without chemotherapy., Results: This study included 47 adult patients. Mean (range) age was 61 (41-79) years; patients were mostly men (37 [79%]). Overall, primary tumors were identified in 37 patients (79%), including all cases with positive nodes involving more than 1 neck level. Patients whose primary tumor was not found tended to have tobacco use history (8/10 vs 13/37 [35%]; difference, 45%; 95% CI, 16%-74%) and absence of ENE (8/10 vs 15/37 [41%]; difference, 39%; 95% CI, 10%-68%). Primary tumor was identified intraoperatively in 18 of 37 patients (49%). SCCs identified intraoperatively were significantly larger than SCCs found on permanent sections only: mean (SE), 1.2 (0.13) cm vs 0.5 (0.1) cm (difference, 0.7 cm; 95% CI, 0.53-1.94). The sensitivity, specificity, positive predictive value, and negative predictive value of intraoperative consultation was 49% (95% CI, 33%-64%), 100% (95% CI, 100%-100%), 100%, and 34% (95% CI, 19%-53%), respectively. Margins were revised in 11 of 18 patients (61%) whose primary tumor was identified intraoperatively (during original procedure) and in 3 of 19 patients (16%) whose primary tumor was identified on permanent pathologic findings only (during a second procedure) (11/18 [61%] vs 3/19 [16%]; difference, 45%; 95% CI, 17%-73%). However, there was no significant difference in the use of adjuvant radiotherapy with or without chemotherapy or need for a second procedure based on intraoperative primary tumor localization., Conclusion and Relevance: In this case series study, the sensitivity and negative predictive value of intraoperative pathology consultation among 47 patients was less than 50%. Given the lack of influence on the need for radiotherapy with or without chemotherapy or second procedure, the practical utility of routine intraoperative frozen section requires further scrutiny.

A subset of head and neck squamous cell carcinomas present solely as metastatic disease in the neck and are of unknown primary origin (SCCUP). Most primary tumors will ultimately be identified, usually in the oropharynx. In a minority of cases, the primary site remains elusive. Here, we examine the role of ancillary testing, including mutational signature analysis (MSA), to help identify likely primary sites in such cases. Twenty-two cases of SCCUP in the neck, collected over a 10-year period, were classified by morphology and viral status; including human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC) and RT-qPCR, as well as Epstein-Barr virus (EBV) testing by EBER-ISH. CD5 and c-KIT (CD117) IHC was done to evaluate for possible thymic origin in all virus-negative cases. Whole exome sequencing, followed by MSA, was used to identify UV signature mutations indicative of cutaneous origin. HPV was identified in 12 of 22 tumors (54.5%), favoring an oropharyngeal origin, and closely associated with nonkeratinizing tumor morphology (Fisher's exact test; p = 0.0002). One tumor with indeterminant morphology had discordant HPV and p16 status (p16+/HPV-). All tumors were EBV-negative. Diffuse expression of CD5 and c-KIT was identified in 1 of 10 virus-negative SCCUPs (10%), suggesting a possible ectopic thymic origin rather than a metastasis. A UV mutational signature, indicating cutaneous origin, was identified in 1 of 10 (10%) virus-negative SCCUPs. A cutaneous auricular primary emerged 3 months after treatment in this patient. Primary tumors became clinically apparent in 2 others (1 hypopharynx, 1 hypopharynx/larynx). Thus, after follow-up, 6 tumors remained unclassifiable as to the possible site of origin (27%). Most SCCUPs of the neck in our series were HPV-associated and thus likely of oropharyngeal origin. UV signature mutation analysis and additional IHC for CD5 and c-KIT for possible thymic origin may aid in further classifying virus-negative unknown primaries. Close clinical inspection of hypopharyngeal mucosa may also be helpful, as a subset of primary tumors later emerged at this site., Competing Interests: Declaration of competing interest The spouse of Wade Thorstad is an employee of Elekta, Inc. (No Elekta products were used for this study and no Electa products are currently used within the Department of Radiation-Oncology at Washington University School of Medicine). Rebecca D. Chernock is a member of Precision Oncology Alliance, Caris Life Sciences (non-financial relationship) and a Steering Committee Member for a Phase III clinical trial of neoadjuvant Pembrolizumab in surgically resectable, locally advanced head and neck squamous cell carcinomas, Merck & Co., Inc. There are no additional potential conflicts of interest relevant to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Surgical cytoreduction for neuroendocrine tumor liver metastasis (NETLM) consistently shows positive long-term outcomes. Despite reservations in guidelines for surgery when the primary tumor is unidentified (UP-NET), this study compared the surgical and oncologic long-term outcomes between patients with these rare cases undergoing cytoreductive surgery and patients who had liver resection for known primaries., Methods: The study identified 32 unknown primary liver metastases (UP-NETLM) in 522 retrospectively evaluated patients who underwent resection of well-differentiated NETLM between January 2000 and December 2020. Tumor and patient characteristics were compared with those in 490 cases of liver metastasis from small intestinal (SI-NETLM) or pancreatic (pNETLM) primaries. Survival analysis was performed to highlight long-term outcome differences. Surgical outcomes were compared between liver resections alone and simultaneous primary resections to assess surgical risk distinctions., Results: The UP-NET patients had fewer NETLMs (p = 0.004), which on the average were larger than SI-NETLMs or pNETLMs (p = 0.002). Expression of Ki-67 was balanced among the groups. Major hepatectomy was performed more often in the UP-NETLM group (p = 0.017). The 10-year survival rate of 53% for UP-NETLM was comparable with that for SI-NETML (58%; p = 0.463) and pNETLMs (47%; p = 0.497). The median hepatic progression-free survival was 26 months for the UP-NETLM patients and 25 months for the SI-NETLM patients compared to 12 months for the pNETLM patients (p < 0.001). Perioperative mortality was lower than 2%, and severe postoperative morbidity occurred in 21%, similarly distributed among all the groups., Conclusion: The surgical risk and long-term outcomes for the UP-NETLM patients were comparable with those for other NETLM cases, affirming the validity of equally aggressive surgical cytoreduction as a therapeutic option in carefully selected cases., (© 2024. Society of Surgical Oncology.)

Competing Interests: CL reports research support from imCORE/Genentech, none of which is related to the treatment of CUP. ER reports grants from Gilead (institutional); travel, accommodation, and expenses fees from Pfizer, Roche, Mundipharma, Eli Lilly, Gilead, and Novartis; and honoraria for lectures and presentations from Eli Lilly, Seagen, and Novartis, none of which are related to the treatment of CUP. FAG reports speaker's bureau and consultancy fees as a medical adviser from Hologic/Biotheranostics.

Background: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP., Methods: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m 2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m 2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m 2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600)., Findings: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed., Interpretation: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients., Funding: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests QX and YS are employees of Canhelp Genomics, Hangzhou, China. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Selective RET inhibitors have shown promise in thyroid cancer (TC) and nonsmall cell lung cancer (NSCLC) harboring RET fusions on next-generation sequencing (NGS), although rarity of the rearrangement has led to limited data for certain tumor types, such as carcinoma of unknown primary. We present a 65-year-old female with no history of malignancy, smoking or radiation exposure, who was found to have an anterior mediastinum malignancy of unknown primary, with metastases to supraclavicular lymph nodes. Core biopsy of the mediastinum revealed poorly differentiated carcinoma, while a biopsy of the thyroid revealed atypia of indeterminate significance (Bethesda III). PD-L1 immunohistochemistry was positive (90%), and liquid NGS revealed mutations in TP53 and the TERT promoter (c.-124C>T), as well as a CCDC6-RET fusion. This genetic profile resembled an anaplastic TC vs. NSCLC primary, although thymic primary and poorly differentiated TC remained on the differential. The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. At a reduced dosage, patient developed transaminitis, and selpercatinib was switched to pralsetinib. Brain MRI showed a nonenhancing temporal lobe signal abnormality, which on biopsy proved to be glioblastoma (GBM) with TERT promoter c.-124C>T mutation and FGFR3-TACC3 fusion by NGS. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To analyze the location, discovery time and possible causes of cases of cervical cystic lymph node metastasis with an unknown primary misdiagnosed as branchial cleft carcinoma. Methods: A retrospective analysis was performed on clinical and pathological data of 15 patients misdiagnosed as branchiogenic carcinoma at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2000 and December 2020. Results: Among the 15 patients, 6 were nasopharyngeal squamous cell carcinoma, 4 tonsil squamous cell carcinoma, 2 tongue root squamous cell carcinoma, 2 hypopharyngeal squamous cell carcinoma and 1 thyroid papillary carcinoma. The median time from the diagnosis of branchial cleft carcinoma to the discovery of primary lesions was 3.58 months (0-76 months). The causes of misdiagnosis might be the lack of experience in the diagnosis and treatment of branchial cleft carcinoma, and not enough attention to comprehensive examination and close follow-up. Conclusions: Different from oropharyngeal cancer reported internationally, the proportion of misdiagnosed cases with nasopharyngeal carcinoma as the primary site in the current article is higher. As a country with a high incidence of nasopharyngeal carcinoma, the examination of nasopharynx should not be taken lightly. Most hidden cases can be found in the comprehensive examination in a short time, while a few cases need long-term follow-up. Finding the primary sites should not rely too much on imaging examination, and we cannot ignore the importance of clinical physical examination.

Cancer of unknown primary (CUP) represents metastatic cancer where the primary site remains unidentified despite standard diagnostic procedures. To determine the tumor origin in such cases, we developed BPformer, a deep learning method integrating the transformer model with prior knowledge of biological pathways. Trained on transcriptomes from 10,410 primary tumors across 32 cancer types, BPformer achieved remarkable accuracy rates of 94%, 92%, and 89% in primary tumors and primary and metastatic sites of metastatic tumors, respectively, surpassing existing methods. Additionally, BPformer was validated in a retrospective study, demonstrating consistency with tumor sites diagnosed through immunohistochemistry and histopathology. Furthermore, BPformer was able to rank pathways based on their contribution to tumor origin identification, which helped to classify oncogenic signaling pathways into those that are highly conservative among different cancers versus those that are highly variable depending on their origins., Competing Interests: Declaration of interests R.Y. and W.Y. are shareholders of Aginome Scientific., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 - 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6-48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6-36.1%, immune cell score [IC]: 8.3-48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 - 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2-36.1% and IC = 9.7-48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes., (© 2024. The Author(s).)

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., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects., Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control., Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022., Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0., Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings., Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%)., Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials., Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Background: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features., Methods: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis., Results: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively)., Conclusion: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

In CUP syndrome (CUP = cancer of unknown primary) there are 1 or more metastases of a primary tumor that cannot be localized despite extensive diagnostics. CUP syndrome accounts for 5% of all human malignancies, making it one of the 10 most common forms of cancer. In addition to inflammatory lymph node enlargement and benign changes such as cervical cysts, lymph node metastases are among the most common cervical masses. Cervical CUP syndrome is a histologically confirmed cervical lymph node metastasis with an unknown primary tumor. In addition to anamnesis, clinical examination and histological confirmation, diagnostics include radiological imaging using PET-CT and panendoscopy with histological primary tumor search. Treatment options include surgical therapy with neck dissection and chemoradiotherapy., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: nein; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background and Objective: Head and neck carcinoma of unknown primary is a diagnostic dilemma. The clinical and imaging workup remains ineffective in two-thirds of patients. Transoral robotic surgery has shown an advantage in the primary detection over the previous standard panendoscopy., Methods: This is an observational cohort study that took place at a large healthcare centre with robotic surgery experience in head and neck over six-years. All included carcinoma of unknown primary patients followed the standard recommendation for primary identification. Final diagnostic step of robotic tongue base mucosectomy with or without tonsillectomy was introduced. The cancer detection rate in tongue base only, the functional outcome and the effect on the cancer pathway were evaluated., Results: Carcinoma of unknown primary was reported in 44 per cent of patients. All identified specimens were human papillomavirus positive. There was no significant effect on functional outcome of swallowing and the national 62-day cancer pathway. Robotic surgery allowed optimum treatment of carcinoma of unknown primary in early nodal disease., Conclusion: Robotic surgery is a useful paradigm in the management of carcinoma of unknown primary. It is safe with minimal morbidity and good functional outcome after the surgery.

Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions. Leveraging cytological images from 57,220 cases at four tertiary hospitals, we developed a deep-learning method for tumor origin differentiation using cytological histology (TORCH) that can identify malignancy and predict tumor origin in both hydrothorax and ascites. We examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets. In both internal and external testing sets, TORCH achieved area under the receiver operating curve values ranging from 0.953 to 0.991 for cancer diagnosis and 0.953 to 0.979 for tumor origin localization. TORCH accurately predicted primary tumor origins, with a top-1 accuracy of 82.6% and top-3 accuracy of 98.9%. Compared with results derived from pathologists, TORCH showed better prediction efficacy (1.677 versus 1.265, P < 0.001), enhancing junior pathologists' diagnostic scores significantly (1.326 versus 1.101, P < 0.001). Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P = 0.006). Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted., (© 2024. The Author(s).)

Context: A major indication for referrals for bone scans (BS) to establish or exclude skeletal metastases. Few patients are referred with clinically indeterminate diagnosis or cancer of unknown primary (CUP), to search for bony metastases or primary tumor., Aims: This study aimed to assess the usefulness or otherwise for BS in such instances., Settings and Design: A retrospective cross-sectional study of BS performed for CUP and indeterminate diagnosis from 2012 to 2016 in the nuclear medicine unit of a tertiary teaching hospital., Subjects and Methods: The study involved reviews of technetium-99m diphosphonate BS for patients with CUP. BSs were reported by nuclear physicians as normal, normal variants, suspicious for metastases or as malignant, and with solitary or multiple skeletal metastases., Statistical Analysis Used: Data were analyzed using SPSS version 21 for descriptive analysis. Continuous data were displayed as means along with their standard deviation; categorical data were tabulated as frequencies and percentages., Results: Of 2156 BS, 42 (0.02%) were eligible. Patients were aged 27-86 years, mainly in the sixth and seventh decades of life. Bone metastases were identified in 14 (33%) of these patients, whereas 17 BS (40%) were normal, BS appeared equivocal in 10 (23.8%)., Conclusions: Single-photon emission computed tomography/computed tomography availability would resolve the clinical dilemma in patients with equivocal and apparently normal BS., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Introduction: A 30-year-old female patient presented with a swelling of a cervical left lymph node measuring 1x3 cm, which had been presenting for three weeks. Lymph node excision revealed a metastasis of a malignant melanoma, but the primary tumor was not found. The guidelines recommend neck dissection and adjuvant systemic or immunotherapy. The patient opted for immunotherapy with pembrolizumab and was tumor-free one year later., Competing Interests: Es bestehen keine Interessenkonflikte., (© 2024 Aerzteverlag medinfo AG.)

Background: The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most common histologic subtype, squamous cell carcinoma, can stem from various tumor primary sites, including the oral cavity, oropharynx, larynx, head and neck skin, lungs, and esophagus. DNA methylation profiles are highly tissue-specific and have been successfully used to classify tissue origin. We therefore developed a support vector machine (SVM) classifier trained with publicly available DNA methylation profiles of commonly cervically metastasizing squamous cell carcinomas (n = 1103) in order to identify the primary tissue of origin of our own cohort of squamous cell hnCUP patient's samples (n = 28). Methylation analysis was performed with Infinium MethylationEPIC v1.0 BeadChip by Illumina., Results: The SVM algorithm achieved the highest overall accuracy of tested classifiers, with 87%. Squamous cell hnCUP samples on DNA methylation level resembled squamous cell carcinomas commonly metastasizing into cervical lymph nodes. The most frequently predicted cancer localization was the oral cavity in 11 cases (39%), followed by the oropharynx and larynx (both 7, 25%), skin (2, 7%), and esophagus (1, 4%). These frequencies concord with the expected distribution of lymph node metastases in epidemiological studies., Conclusions: On DNA methylation level, hnCUP is comparable to primary tumor tissue cancer types that commonly metastasize to cervical lymph nodes. Our SVM-based classifier can accurately predict these cancers' tissues of origin and could significantly reduce the invasiveness of hnCUP diagnostics and enable a more precise therapy after clinical validation., (© 2024. The Author(s).)

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., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Carcinoma of unknown primary (CUP) remains an important tumor entity and a disproportionate cause of cancer mortality. Little is known about the contemporary clinical characteristics, treatment patterns, and outcomes of CUP patients based on updated international classification guidelines. We evaluated a contemporary CUP cohort to provide insight into current clinical practice and the impact of tissue of origin assignment, site-specific and empirical therapy in a real-world setting., Methods: We conducted a retrospective cohort study of CUP patients, as defined by the updated European Society of Medical Oncology (ESMO) 2023 guidelines, across three tertiary referral centers in Australia between 2015 and 2022. We analyzed clinical characteristics, treatment patterns, and survival outcomes using the Kaplan-Meier method and Cox regression proportional hazard model between favorable and unfavorable risk groups., Results: We identified a total of 123 CUP patients (n = 86 unfavorable, n = 37 favorable risk as per the 2023 ESMO guidelines). Sixty-four patients (52%) were assigned a tissue of origin by the treating clinician. Median progression free survival (PFS) was 6.8 (95% confidence interval (CI) 5.1-12.1) months and overall survival (OS) 10.2 (95% CI 6.0-18.5) months. Unfavorable risk (hazard ratio [HR] 2.9, p = 0.006), poor performance status (HR 2.8, p < 0.001), and non-squamous histology (HR 2.5, p < 0.05) were associated with poor survival outcome. A total of 70 patients (57%) proceeded to systemic therapy. In patients with non-squamous histology and unfavorable risk, site-specific therapy compared to empirical chemotherapy did not improve outcome (median OS 8.2 vs. 11.8 months, p = 0.7)., Conclusions: In this real-world cohort, CUP presentations were heterogenous. Overall survival and rates of systemic treatment were poor. Poor performance status and unfavorable risk were associated with worse survival. For most patients, site-specific therapy did not improve survival outcome. Improved and timely access to diagnostic tests and therapeutics for this group of patients is urgently required., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis., Purpose: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone., Methods: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors., Results: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years)., Limitations: Lack of an external data set for model validation., Conclusion/relevance: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients., Competing Interests: Conflicts of interest Paul Nghiem reports personal fees from Rain Therapeutics, EMD Serono, Pfizer, and Merck; grants from EMD Serono and Bristol-Myers Squibb to his institution outside the submitted work; and a patent for Merkel cell polyomavirus T antigen–specific T-cell receptors and uses thereof pending (University of Washington), as well as a patent for novel epitopes as T-cell targets in Merkel cell carcinoma pending (University of Denmark and University of Washington). No other disclosures were reported., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Metastatic carcinoma of unknown primary origin to the head and neck lymph nodes (HNCUP) engenders unique diagnostic considerations. In many cases, the detection of a high-risk human papillomavirus (HR-HPV) unearths an occult oropharyngeal squamous cell carcinoma (SCC). In metastatic HR-HPV-independent carcinomas, other primary sites should be considered, including cutaneous malignancies that can mimic HR-HPV-associated SCC. In this context, ultraviolet (UV) signature mutations, defined as ≥ 60% C→T substitutions with ≥ 5% CC→TT substitutions at dipyrimidine sites, identified in tumors arising on sun exposed areas, are an attractive and underused tool in the setting of metastatic HNCUP., Methods: A retrospective review of institutional records focused on cases of HR-HPV negative HNCUP was conducted. All cases were subjected to next generation sequencing analysis to assess UV signature mutations., Results: We identified 14 HR-HPV negative metastatic HNCUP to either the cervical or parotid gland lymph nodes, of which, 11 (11/14, 79%) had UV signature mutations, including 4 (4/10, 40%) p16 positive cases. All UV signature mutation positive cases had at least one significant TP53 mutation and greater than 20 unique gene mutations., Conclusion: The management of metastatic cutaneous carcinomas significantly differs from other HNCUP especially metastatic HR-HPV-associated SCC; therefore, the observation of a high percentage of C→T with CC →TT substitutions should be routinely incorporated in next generation sequencing reports of HNCUP. UV mutational signatures testing is a robust diagnostic tool that can be utilized in daily clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancers of unknown primary (CUP) exhibit significant cellular heterogeneity and malignancy, which poses significant challenges for diagnosis and treatment. Recent years have seen deeper insights into the imaging, pathology, and genetic characteristics of CUP, driven by interdisciplinary collaboration and the evolution of diagnostic and therapeutic strategies. However, due to their insidious onset, lack of evidence-based medicine, and limited clinical understanding, diagnosing and treating CUP remain a significant challenge. To inspire more creative and fantastic research, herein, we report and highlight recent advances in the diagnosis and therapeutic strategies of CUP. Specifically, we discuss advanced diagnostic technologies, including 12-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) or 68 Ga-FAPI (fibroblast activation protein inhibitor) PET/CT, liquid biopsy, molecular diagnostics, self-assembling nanotechnology, and artificial intelligence (AI). In particular, the discussion will extend to the effective treatment techniques currently available, such as targeted therapies, immunotherapies, and bio-nanotechnology-based therapeutics. Finally, a novel perspective on the challenges and directions for future CUP diagnostic and therapeutic strategies is discussed.

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., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

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., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Cancer of unknown primary (CUP) is a very challenging disease, accounting for 2% to 9% of all new cancer cases. This type of tumor is a heterogeneous tumor whose primary site cannot be determined by standard examination. It has the characteristics of early metastasis, strong aggressiveness, and unpredictable mode of metastasis. Studies have shown that there is no consensus on the treatment of CUP and that there is a wide range of individual differences. In most cases, surgical removal of tumor is the most typical treatment for pelvic tumors. Herein, we report a case of a large pelvic tumor of unknown origin that had compressed the sigmoid colon and ureter and was completely removed by surgery. Postoperative diagnosis was pelvic metastatic squamous cell carcinoma., Case Summary: A 68-year-old man with pelvic tumor who initially complained of recurrent low back pain and painful urination. The mass was initially diagnosed as a pelvic tumor of unknown origin. The patient underwent complete resection of the tumor by laparotomy. The tumor was pathologically diagnosed as squamous cell carcinoma., Conclusion: Based on the treatment experience of this case, surgery alone cannot improve the poor prognosis of CUP. Since chemotherapy and immunotherapy have achieved promising efficacy in various cancers, and immunotherapy has the characteristics of low side effects and good tolerability, we recommend that patients with CUP should receive chemotherapy and/or immunotherapy for better survival outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Despite a standardized diagnostic examination, cancer of unknown primary (CUP) is a rare metastatic malignancy with an unidentified tissue of origin (TOO). Patients diagnosed with CUP are typically treated with empiric chemotherapy, although their prognosis is worse than those with metastatic cancer of a known origin. TOO identification of CUP has been employed in precision medicine, and subsequent site-specific therapy is clinically helpful. For example, molecular profiling, including genomic profiling, gene expression profiling, epigenetics and proteins, has facilitated TOO identification. Moreover, machine learning has improved identification accuracy, and non-invasive methods, such as liquid biopsy and image omics, are gaining momentum. However, the heterogeneity in prediction accuracy, sample requirements and technical fundamentals among the various techniques is noteworthy. Accordingly, we systematically reviewed the development and limitations of novel TOO identification methods, compared their pros and cons and assessed their potential clinical usefulness. Our study may help patients shift from empirical to customized care and improve their prognoses., (© The Author(s) 2024. Published by Oxford University Press.)

Bilateral retinal metastasis is a rare disease that represents less than 1% of ocular metastases. Additionally, the prevalence of ocular metastases overall is only 5% to 10%. It is uncommonly found due to the absence of a lymphatic system in the eye. Ocular metastasis is spread hematogenously and the retina only receives 5% of blood flow, contributing to the rarity of this condition. Retinal metastasis has been reported to mimic symptoms of retinitis which include watery eye discharge, conjunctival injection and pain with ocular movement which leads to a harder diagnosis. Treatment options for retinal metastasis include systemic chemotherapy, intravitreal chemotherapy, and plaque radiotherapy. However, despite treatment, retinal metastasis often has a poor prognosis. This is a case of a 65-year-old woman with a history of breast carcinoma status post mastectomy who initially presented with metastatic infiltration of the lung and liver. However, she later developed an interesting case of retinal metastasis, which presented as symptoms of retinitis and indicated widespread dissemination of an unknown primary neoplasm., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Signet ring cells (SRCs) may be observed in carcinomas from multiple primary sites. Elucidating unknown primaries from metastases with SRCs represents a diagnostic challenge. This study examined morphologic characteristics of adenocarcinomas with SRCs from stablished primary sites and described objective features, which can aid in identifying the site of origin., Methods: The series encompasses 257 cases of adenocarcinomas with SRCs from gastroesophageal junction (GEJ, n = 38), stomach (n = 48), pancreatobiliary system (n = 16), colorectum (n = 40), appendix (n = 32), breast (n = 41), and lung (n = 42). H&E sections were examined and scored using architectural and cytologic criteria. Morphometric analysis was performed using QuPath software., Results: Extracellular mucin was more abundant in GEJ, colorectal, and appendiceal carcinomas. Poorly cohesive morphology was the most frequent pattern in gastric and breast carcinomas. The cytoplasmic mucin/vacuole was predominantly clear and targetoid in breast carcinomas. Breast and gastric carcinomas showed the highest nuclear to cytoplasmic (N/C) ratio, whereas appendiceal carcinoma the lowest., Conclusion: Morphological evaluation (extracellular mucin, architectural patterns, and the nature of cytoplasmic mucin/vacuole) represents an important step to determine the cancer site of origin in adenocarcinomas with SRCs and guides further ancillary studies. Cytological morphometry may help further refine morphological criteria and facilitate the construction of digital-pathology algorithms., (© 2023 S. Karger AG, Basel.)

Rationale: Cancer with unknown primary site is a kind of disease that is difficult to deal with clinically, accounting for 2% to 9% of all newly diagnosed cancer cases. Here, we report such a case with pelvic metastatic squamous cell carcinoma of an unknown primary site and review the relevant literature., Patient Concerns Diagnoses: A 43-year-old Chinese female patient was referred to our hospital and initially diagnosed as "malignant tumor of right adnexal area?, obstruction of right ureter, secondary hydronephrosis"., Interventions: Thereafter cytoreductive surgery was performed which included a total hysterectomy, left adnexectomy, partial omentum resection, pelvic lymph node dissection, and para-aortic lymph node dissection. The primary lesion could not be identified by supplementary examination and postoperative pathology. The patient was diagnosed as pelvic metastatic squamous cell carcinoma whose primary site was unknown. To prevent a recurrence, we administered adjuvant chemotherapy for the patient., Outcomes: The patient was followed up after treatment, complete remission has been maintained for 72 months, and no recurrence or metastasis has been found., Lessons: Our case demonstrates that surgery combined with chemotherapy could be helpful for pelvic metastatic squamous cell carcinoma of unknown primary site., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study., Materials and Methods: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability., Results: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAF V600E , EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities., Conclusions: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO., Competing Interests: Disclosure CBW reports honoraria from Bayer, Celgene, Ipsen, Servier, Taiho, and F. Hoffmann-La Roche Ltd, has participated in advisory boards for Celgene, Shire/Baxalta, Rafael Pharmaceuticals, RedHill BioPharma, and F. Hoffmann-La Roche Ltd, and has received travel/accommodation expenses from Bayer, Celgene, RedHill BioPharma, F. Hoffmann-La Roche Ltd, Servier, and Taiho. JFG is an employee of and has stocks/shares in F. Hoffmann-La Roche Ltd. CP has received an institutional research grant from F. Hoffmann-La Roche Ltd, works as a study pathologist for the CUPISCO trial, and has received travel coverage and remuneration for study-related work such as histopathology reviews for patients in screening and in molecular tumor boards, for the benefit of her employer. ARK, NCh, and GDP are employees of and hold stocks/shares in F. Hoffmann-La Roche Ltd. AB was an employee of F. Hoffmann-La Roche Ltd. TB has received an institutional research grant from F. Hoffmann-La Roche Ltd, works as a study oncologist for the CUPISCO trial, and has received coverage for study-related travel and remuneration for study-related work in a molecular tumor board for the benefit of his employer. NCo has participated in an advisory board for RedX Pharmaceuticals and has received institutional research funding from AstraZeneca, Orion, F. Hoffmann-La Roche Ltd, Taiho, GSK, Novartis, Starpharma, Bayer, Eisai, UCB, RedX Pharmaceuticals, Stemline Therapeutics, Boehringer Ingelheim, Merck, Avacta Pharmaceuticals, and Tarveda Therapeutics. EH is an employee of and holds stocks/shares in F. Hoffmann-La Roche Ltd. DXJ is an employee of Foundation Medicine, Inc. and holds stocks/shares in F. Hoffmann-La Roche Ltd. FL has received institutional research funding from F. Hoffmann-La Roche Ltd, Amgen, and Merck, has received travel/accommodation expenses from F. Hoffmann-La Roche Ltd and Merck, has participated in an advisory board for F. Hoffmann-La Roche Ltd, Amgen, Merck, Sanofi, and Servier, and has participated in a speaker bureau/expert testimony for F. Hoffmann-La Roche Ltd and Sanofi. LM has received travel/accommodation expenses from F. Hoffmann-La Roche Ltd and BeiGene. HM has received honoraria from or has participated in advisory boards for F. Hoffmann-La Roche Ltd, Ventana, Definiens, Merck, BMS, Astellas, Johnson & Johnson, Bayer, Ipsen, and Amgen, has received travel/accommodation expenses from F. Hoffmann-La Roche Ltd and Definiens, and has received institutional research funding from F. Hoffmann-La Roche Ltd. JSR has received honoraria from, holds stocks/shares in, and has a leadership role in Foundation Medicine, Inc. ESS is an employee of Foundation Medicine, Inc. and holds stocks/shares in F. Hoffmann-La Roche Ltd. RWT has received honoraria from Merck Serono Australia. AK has received honoraria from F. Hoffmann-La Roche Ltd, Daiichi Sankyo, and AbbVie, honoraria to his institution from F. Hoffmann-La Roche Ltd and Bayer, has a leadership role in F. Hoffmann-La Roche Ltd, has received institutional research funding from Merck and Bayer, has received travel/accommodation expenses from F. Hoffmann-La Roche Ltd, Celgene, and Daiichi Sankyo, and has acted as an advisory consultant for Daiichi Sankyo, BMS, and AbbVie. All authors received research support (medical writing support) from F. Hoffmann-La Roche Ltd., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)