[Cervical CUP Syndrome: Diagnosis and Therapy]. / Zervikales CUP-Syndrom: Diagnostik und Therapie.

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.

Retrospective analysis of clinical characteristics and outcomes of patients with carcinoma of unknown primary from three tertiary centers in Australia.

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.

Bone metastatic cancer of unknown primary at initial presentation

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 (AU)

New techniques to identify the tissue of origin for cancer of unknown primary in the era of precision medicine: progress and challenges.

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.

Bone metastatic cancer of unknown primary at initial presentation.

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.

The practical utility of AI-assisted molecular profiling in the diagnosis and management of cancer of unknown primary: an updated review.

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.

Positive factors on survival of head and neck cancer of unknown primary: what the clinician can do.

BACKGROUND: Management of patients with head and neck cancer of unknown primary (HNCUP) is challenging. AIMS/OBJECTIVES: 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. MATERIAL AND METHODS: We retrospectively analyzed patients with HNCUP between 2003 and 2016. Univariate and multivariate analyses were used to investigate predictors of overall survival (OS). RESULTS: 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. CONCLUSION AND SIGNIFICANCE: 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.

Machine learning for genetics-based classification and treatment response prediction in cancer of unknown primary.

Cancer of unknown primary (CUP) is a type of cancer that cannot be traced back to its primary site and accounts for 3-5% of all cancers. Established targeted therapies are lacking for CUP, leading to generally poor outcomes. We developed OncoNPC, a machine-learning classifier trained on targeted next-generation sequencing (NGS) data from 36,445 tumors across 22 cancer types from three institutions. Oncology NGS-based primary cancer-type classifier (OncoNPC) achieved a weighted F1 score of 0.942 for high confidence predictions ([Formula: see text]) on held-out tumor samples, which made up 65.2% of all the held-out samples. When applied to 971 CUP tumors collected at the Dana-Farber Cancer Institute, OncoNPC predicted primary cancer types with high confidence in 41.2% of the tumors. OncoNPC also identified CUP subgroups with significantly higher polygenic germline risk for the predicted cancer types and with significantly different survival outcomes. Notably, patients with CUP who received first palliative intent treatments concordant with their OncoNPC-predicted cancers had significantly better outcomes (hazard ratio (HR) = 0.348; 95% confidence interval (CI) = 0.210-0.570; P = [Formula: see text]). Furthermore, OncoNPC enabled a 2.2-fold increase in patients with CUP who could have received genomically guided therapies. OncoNPC thus provides evidence of distinct CUP subgroups and offers the potential for clinical decision support for managing patients with CUP.

Carcinoma of unknown primary (CUP): an update for histopathologists.

Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. In this review, we provide histopathologists with diagnostic practice points which contribute to identifying the primary origin in such cases. We present the current clinical evaluation and management from the point of view of the oncologist. We discuss the role of the pathologist in the diagnostic pathway including the control of pre-analytical conditions, assessment of sample adequacy, diagnosis of cancer including diagnostic pitfalls, and evaluation of prognostic and predictive markers. An integrated diagnostic report is ideal in cases of CUP, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. This highly specialized evolving area ultimately leads to personalized oncology and potentially improved outcomes for patients.

A comparison between p16-positive head and neck cancer of unknown primary (HPV-HNCUP) and oropharyngeal squamous cell carcinoma (HPV-OPSCC): are they the same disease?

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.

Immunochemotherapy achieved a complete response for metastatic adenocarcinoma of unknown primary based on gene expression profiling: a case report and review of the literature.

Background: Cancer of unknown primary (CUP) is a malignant and aggressive tumor whose primary origin is still unknown despite thorough evaluation. CUP can be life-threatening with a median overall survival of less than 1 year based on empirical chemotherapy. Gene detection technology advances the driver gene detection of malignant tumors and the appropriate precise therapy. Immunotherapy has ushered in a new era in cancer therapy, changing the way advanced tumors, including CUP, are treated. Combined with comprehensive clinical and pathological investigations, molecular analysis of the original tissue and detection of potential driver mutations may provide therapeutic recommendations for CUP. Case presentation: A 52-year-old female was admitted to hospital for dull abdominal pain, with peripancreatic lesions below the caudate lobe of the liver and posterior peritoneal lymph nodes enlargement. Conventional biopsy under endoscopic ultrasonography and laparoscopic biopsy both revealed poorly differentiated adenocarcinoma based on immunohistochemical series. To help identify tumor origin and molecular characteristics, 90-gene expression assay, tumor gene expression profiling with Next-generation sequencing (NGS) method and Immunohistochemical expression of PD-L1 were employed. Although no gastroesophageal lesions discovered by gastroenteroscopy, the 90-gene expression assay yielded a similarity score and prompted the most likely primary site was gastric/esophagus cancer. NGS revealed high TMB (19.3mutations/Mb) but no druggable driver genes identified. The Dako PD-L1 22C3 assay IHC assay for PD-L1 expression revealed a tumor proportion score (TPS) of 35%. Given the presence of negative predictive biomarkers for immunotherapy, including adenomatous polyposis coli (APC) c.646C>T mutation at exon 7 and Janus kinase 1(JAK1), the patient received immunochemotherapy instead of immunotherapy alone. She was successfully treated with nivolumab plus carboplatin and albumin-bound nanoparticle paclitaxel for six cycles and nivolumab maintenance, which achieved a complete response (CR) maintained for 2 years without severe adverse events. Conclusions: This case highlights the value of multidisciplinary diagnosis and individual precision treatment in CUP. Further investigation is needed as an individualized treatment approach combining immunotherapy and chemotherapy based on tumor molecular characteristics and immunotherapy predictors is expected to improve the outcome of CUP therapy.

Six-year experience of Australia's first dedicated cancer of unknown primary clinic.

BACKGROUND: Diagnosis and management of cancers of unknown primary (CUP) remain challenging. This study examines the referral patterns, management and outcomes of patients referred to Australia's first dedicated CUP clinic. METHODS: Retrospective medical record review was conducted for patients seen at the Peter MacCallum Cancer Centre CUP clinic between July 2014 and August 2020. Overall survival (OS) was analysed for patients with a CUP diagnosis where treatment information was available. RESULTS: Of 361 patients referred, fewer than half had completed diagnostic work-up at the time of referral. A diagnosis of CUP was established in 137 (38%), malignancy other than CUP in 177 (49%) and benign pathology in 36 (10%) patients. Genomic testing was successfully completed in 62% of patients with initial provisional CUP and impacted management in 32% by identifying a tissue of origin or actionable genomic alteration. The use of site-specific, targeted therapy or immunotherapy was independently associated with longer OS compared to empirical chemotherapy. CONCLUSION: Our specialised CUP clinic facilitated diagnostic work-up among patients with suspected malignancy and provided access to genomic testing and clinical trials for patients with a CUP diagnosis, all of which are important to improve outcomes in this patient population.

[Peritoneal carcinomatosis secondary to CUP syndrome : Diagnosis and indications for multimodal treatment]. / Peritonealkarzinose beim CUP­Syndrom : Diagnostik und Indikationsstellung für die multimodale Therapie.

CLINICAL PROBLEM: Peritoneal carcinomatosis secondary to cancer of unknown primary (CUP) syndrome is a rare entity for which there are no uniform treatment recommendations or guidelines. The median survival time is 3 months. DIAGNOSIS: Computed tomography (CT), magnetic resonance imaging (MRI), and 18F­FDG positron emission tomography (PET)/CT are valid imaging modalities for the detection of peritoneal carcinomatosis. The sensitivity of all techniques is highest for large, macronodular peritoneal carcinomatosis manifestations. A limitation of all imaging techniques is limited and small-nodular peritoneal carcinomatosis. Also, peritoneal metastasis in the small bowel mesentery or diaphragmatic domes can only be visualized with low sensitivity. Therefore, exploratory laparoscopy should be considered as the next diagnostic step. In half of these cases an unnecessary laparotomy can be avoided, because the laparoscopy revealed diffuse, small-nodule involvement of the small bowel wall and thus an irresectable situation. TREATMENT: In selected patients, performing complete cytoreduction followed by hyperthermic intra-abdominal chemotherapy (HIPEC) is a good therapeutic option. Therefore, the identification of the extent of peritoneal tumor manifestation as accurately as possible is important for the definition of the increasingly complex oncological therapy strategies.

Clinical practice guidelines for management of head and neck squamous cell carcinoma of unknown primary: an AGREE II appraisal.

IMPORTANCE: Squamous cell carcinoma without a known primary is an uncommon form of head and neck cancer that requires multidisciplinary collaboration for effective management. OBJECTIVE: To evaluate the quality of clinical practice guidelines (CPG) using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. DESIGN: A systematic literature search was performed to identify CPGs pertaining to the diagnosis and treatment of head and neck squamous cell carcinoma of unknown primary (HNSCCUP). Data were abstracted from guidelines meeting inclusion criteria and appraised by four independent reviewers in the six domains of quality defined by the AGREE II. SETTING: Online database. PARTICIPANTS: None. EXPOSURE: None. MAIN OUTCOME(S) AND MEASURE(S): Quality domain scores and intraclass correlation coefficients (ICC) were calculated across domains to qualify inter-rater reliability. RESULTS: Seven guidelines met inclusion criteria. Two guidelines achieved a score of > 60% in five or more AGREE II quality domains to gain designation as 'high'-quality content. One "average-quality" guideline authored by the ENT UK Head and Neck Society Council achieved a score of > 60% in three quality domains. The remaining four CPGs demonstrated low-quality content, with deficits most pronounced in domains 3 and 5, suggesting a lack of rigorously developed and clinically applicable information. CONCLUSIONS AND RELEVANCE: As the diagnosis and treatment of head and neck cancer continues to evolve, identification of high-quality guidelines will become increasingly important. The authors recommend consulting HNSCCUP guidelines from the National Institute for Health and Care Excellence (NICE) or the American Society of Clinical Oncology (ASCO). TRIAL REGISTRATION: None.

[CUP syndrome-diagnostics from the perspective of pathology]. / CUP-Syndrom ­ Diagnostik aus Sicht der Pathologie.

PROBLEM: Histologic and immunohistologic workup of tumor material from metastases of a previously unknown primary tumor is important for identifying their origin, but is often insufficient for this purpose without clinical oncologic and radiologic evaluation. PROCEDURE: In the initial cancer of unknown primary (CUP) situation, histologic and immunohistochemical workup together with clinicoradiologic correlations contribute significantly to the identification of the primary tumor. There are now accepted guidelines to follow when there is an initial CUP situation. Molecular diagnostic tools can be used to investigate changes at the nucleic acid level, which can provide clues about the primary tumor, including potential targets for therapy. If, despite broad and interdisciplinary diagnostics, it is not possible to identify the primary tumor, the diagnosis is CUP syndrome. If a true CUP situation is present, it is important to assign the tumor to a tumor class or a specific therapy-sensitive subgroup as best as possible so that the best possible treatment can be given. However, for a final assignment to a primary tumor or a final classification as CUP, a comparison with medical oncological and imaging findings is indispensable. CONCLUSION: When CUP is suspected, close interdisciplinary collaboration between pathology, medical oncology, and imaging is essential to achieve a viable classification as CUP or identification of a presumptive primary tumor, in the interest of providing the most specific and effective therapy for affected individuals.

Cancer of unknown primary (CUP) through the lens of precision oncology: a single institution perspective.

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.