Unknown Primary Site Research Articles

Abstract 820: Genomics based personalized oncology of cancer of unknown primary

Abstract Cancers of unknown primary site (CUPs) represent a heterogeneous group of metastatic tumors, which accounts for 3-5% of malignancies. Due to the poor prognosis and limited local and systemic treatment options, there is an urgent need for improvement of molecularly driven treatment strategies. We investigated the molecular profile and clinical course of 70 patients enrolled in a prospective precision oncology registry trial conducted by the National Center for Tumor Diseases (NCT) Heidelberg/Dresden and the German Cancer Consortium (DKTK) that addresses younger adults with advanced-stage cancer across histologies as well as patients with rare tumors (NCT/DKTK MASTER). Molecular analyses included whole genome sequencing (WGS, n=29), whole exome sequencing (WES, n=41) and transcriptome analysis (n=55). All patients were diagnosed with CUP-syndrome, 61/70 (87.1%) of diagnoses fulfilled the ESMO Clinical Practice Guidelines. Progression free survival (PFS) of the first treatment based on MASTER (PFS2) was compared to the PFS of the last prior systemic treatment (PFS1) in each individual patient. Within the coding sequence, we identified 0 to 1386 nonsynonymous point mutations (SNVs, median=41) and 0 to 38 insertions/deletions (indels, median=3) per sample. Hypermutation (≥100 SNVs and indels) was observed in 14 samples. Mutations of TP53 and KRAS were significantly enriched. Analysis of copy-number changes (CNVs) was performed in 51 samples (27 WGS and 24 WES) and revealed complex CNV profiles in most cases. Gains and losses involved single arms or whole chromosomes. Gains in chromosome 8q, 1q and 7 and losses in chromosome 6q and 17p occurred in more than 40% of the patients. Fusions of EML4-ALK and FGFR2 were found in three and six cases, respectively. In one case, pathological reevaluation for NUT midline carcinoma was recommended based on a NUTM1-MXI1 fusion. In total, pathological reevaluation based on characteristic genetic events was recommended in five cases. Germline analysis of 70 cases revealed five pathogenic variants (ACMG Class 5) in CHEK2, BRCA1, CDKN2A, NBN and ERCC3. In addition, one likely pathogenic variant (ACMG Class 4) was found in FH. The molecular tumor board recommended targeted therapy in 56/70 (80.0%) patients which could be applied in 20/56 (35.7%) cases. The molecularly driven treatment approaches translated into a median PFS2/1 ratio of 2.25 (n=17). Median PFS1 was 89 days (range 31-304, n=17) compared to a median PFS2 of 180 days (range 50-805, n=17). For three patients in which PFS1 could not be determined median PFS2 was 305 days (range 182-336). We demonstrate that a comprehensive molecular analysis of CUPs provides clinically relevant information and additional, molecularly stratified treatment approaches in many cases. These targeted therapies can be highly beneficial even in heavily pretreated patients. Citation Format: Maximilian Werner, Lino Möhrmann, Małgorzata Oleś, Andreas Mock, Arne Jahn, Simon Kreutzfeldt, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Daniela Richter, Gina Rüter, Ivan Jelas, Rainer Hamacher, Johanna Falkenhorst, Sebastian Wagner, Christian Brandts, Melanie Börries, Anna Illert, Klaus Metzeler, Benedikt Westphalen, Alexander Desuki, Thomas Kindler, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Peter Horak, Christoph Heining, Stefan Fröhling, Hanno Glimm. Genomics based personalized oncology of cancer of unknown primary [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 820.

Abstract 821: Comprehensive genomic analysis of rare cancers: Results of the MASTER precision oncology trial of the German Cancer Consortium

Abstract Comprehensive molecular profiling can be successfully applied to guide targeted treatment in cancer patients, an approach commonly referred to as precision oncology. Over the past years, several clinical trials that employed subgenomic molecular profiling have demonstrated that molecularly informed decision-making across tumor entities is associated with improved clinical outcome in approximately one third of patients. To investigate the feasibility and clinical relevance of comprehensive genomic analysis, i.e. whole-exome/genome sequencing (WES/WGS) and RNA sequencing (RNA-seq), in younger adults with advanced-stage cancer across all histologies and patients with rare tumors, we established MASTER (Molecularly Aided Stratification for Tumor Eradication Research) - a prospective, multicenter precision oncology platform - at NCT Heidelberg/Dresden in 2013, which was extended to the German Cancer Consortium (DKTK) in 2016. Based on a standardized workflow, we have analyzed more than 1,700 poor-prognosis (median overall survival, 12 months) patients with advanced, heavily pretreated (median number of prior therapies, n=2) malignancies representing a broad spectrum of rare histopathologic entities. We here report the actionable findings and clinical outcomes for the first 1,311 patients discussed in cross-institutional molecular tumor board (MTB) conferences. Each MTB recommendation was based on the individual molecular profile and specific predictive molecular biomarkers identified by WES/WGS and RNA-seq. In addition to DNA alterations (single-nucleotide variants, small insertions/deletions, copy number alterations), we also used alterations identified by RNA-seq (gene fusions, aberrant gene expression) to support clinical decision-making. We categorized therapy recommendations into seven different intervention baskets and assigned evidence levels to each recommendation according to a dedicated NCT/DKTK classification system, which addresses the complexity of evaluating predictive molecular biomarkers in clinical routine. MTB recommendations were implemented in one third of cases, and overall response and disease control rates on molecularly guided treatment were improved compared to prior systemic therapies, which translated into a progression-free survival ratio of greater than 1.3 in a significant proportion of patients. Furthermore, comprehensive genomic profiling in combination with histopathologic reevaluation allowed reclassification of approximately 4% of cases, in particular soft-tissue sarcomas not otherwise specified and carcinomas of unknown primary site. This prospective study demonstrates that comprehensive molecular profiling based on WES/WGS and RNA-seq in a multiinstitutional clinical setting creates meaningful therapeutic opportunities for patients with rare cancers. Our data demonstrate the added benefit of germline and RNA analysis, providing a rationale for their routine clinical implementation. Current and future activities of the MASTER network are focused on the standardization of variant classification and evidence levels in MTB conferences, the implementation of molecularly stratified basket trials, and the integration of additional layers of patient characterization. Citation Format: Peter Horak, Christoph Heining, Andreas Mock, Simon Kreutzfeldt, Andreas Lassmann, Lino Möhrmann, Jennifer Hüllein, Dorothea Hanf, Arne Jahn, Leo Ruhnke, Laura Gieldon, Christoph E. Heilig, Veronica Teleanu, Martina Fröhlich, Sebastian Uhrig, Katja Beck, Daniela Richter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meissburger, Frederick Klauschen, Ulrich Keilholz, Sebastian Ochsenreither, Gunnar Folprecht, Jens Siveke, Sebastian Bauer, Thomas Kindler, Christian Brandts, Melanie Boerries, Anna L. Illert, Nikolas von Bubnoff, Karsten Spiekermann, Philipp J. Jost, Klaus Schulze-Osthoff, Michael Bitzer, Peter Schirmacher, Christof von Kalle, Richard F. Schlenk, Barbara Klink, Barbara Hutter, Daniel Hübschmann, Albrecht Stenzinger, Wilko Weichert, Evelin Schröck, Benedikt Brors, Hanno Glimm, Stefan Fröhling, German Cancer Consortium (DKTK). Comprehensive genomic analysis of rare cancers: Results of the MASTER precision oncology trial of the German Cancer Consortium [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 821.

A Deep Learning Framework to Predict Tumor Tissue-of-Origin Based on Copy Number Alteration.

Cancer of unknown primary site (CUPS) is a type of metastatic tumor for which the sites of tumor origin cannot be determined. Precise diagnosis of the tissue origin for metastatic CUPS is crucial for developing treatment schemes to improve patient prognosis. Recently, there have been many studies using various cancer biomarkers to predict the tissue-of-origin (TOO) of CUPS. However, only a very few of them use copy number alteration (CNA) to trance TOO. In this paper, a two-step computational framework called CNA_origin is introduced to predict the tissue-of-origin of a tumor from its gene CNA levels. CNA_origin set up an intellectual deep-learning network mainly composed of an autoencoder and a convolution neural network (CNN). Based on real datasets released from the public database, CNA_origin had an overall accuracy of 83.81% on 10-fold cross-validation and 79% on independent datasets for predicting tumor origin, which improved the accuracy by 7.75 and 9.72% compared with the method published in a previous paper. Our results suggested that the autoencoder model can extract key characteristics of CNA and that the CNN classifier model developed in this study can predict the origin of tumors robustly and effectively. CNA_origin was written in Python and can be downloaded from https://github.com/YingLianghnu/CNA_origin.

Original Article Non-Hematological Malignancies Seeding in Bone Marrow

Background: Bone marrow is the site of origin for primary haematological malignancies and is the third common preferred site metastasized by the solid tumors. The malignant infiltration of the hematopoietic tissue alters the clinical course of disease, response of the treatment and influences the overall survival. The aim of this study was to assess pattern of bone marrow involvement by different solid tumors and their correlation with hematological parameters.
 Methods: In this retrospective study, 8064 bone marrow examinations from Jan 2011-Aug 2017 at tertiary health and research centre of Northern India were evaluated to access spectrum of different solid tumors infiltrating the bone marrow alongwith their clinical, hematological and histopathological findings.
 Result: Total 38 cases of non-hematological malignancies metastasizing to bone marrow were evaluated with main indications of lytic lesions, cytopenia and Pyrexia of Unknown Origin. The most common metastasis were adenocarcinoma of prostate and lung. In 33 cases, the clinical, cytomorphological and immunohistochemical analysis findings were correlated to know primary site, while in remaining five patients, even after complete diagnostic evaluation, the definitive origin could not be ascertained, therefore categorized as Carcinoma of Unknown Primary Site (CUPS).
 Conclusion: Our series showed that anemia as commonest parameter, followed by leukopenia, thrombocytopenia. Many cases were misdiagnosed as multiple myeloma due to lytic lesion, anemia and hypercalcemia. We concluded that unexplained cytopenia are strong indicators of bone marrow examination; an easy, convenient, sensitive, effective procedure of staging of tumor, monitoring the course and prognosis of solid tumors.

Clinical Impact of F-18 FDG PET-CT on Biopsy Site Selection in Patients with Suspected Bone Metastasis of Unknown Primary Site.

We investigated the clinical role of F-18 fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in the identification of the primary site and the selection of the optimal biopsy site in patients with suspected bone metastasis of unknown primary site. The patients with suspected bone metastasis who underwent PET-CT for evaluation of primary site were enrolled in this study. The primary sites were identified by the histopathologic or imaging studies and were classified according to the FDG uptake positivity of the primary site. To evaluate the guiding capability of PET-CT in biopsy site selection, we statistically analyzed whether the biopsy site could be affected according to the presence of extra-skeletal FDG uptake. Among 74 enrolled patients, 51 patients had a metastatic bone disease. The primary site was identified in 48 of 51 patients (94.1%). Forty-six patients were eligible to test the association of clinical choice of biopsy site with PET positivity of extra-skeletal lesion. The extra-skeletal biopsies were done in 42 out of 43 patients with positive extra-skeletal uptake lesions. Bone biopsies were inevitably performed in the other three patients without extra-skeletal uptake lesions. The association came out to be significant (Fisher's exact test, P < 0.001). F-18 FDG PET-CT significantly contributed not only to identify the primary site but also to suggest optimal biopsy sites in patients with suspected bone metastasis.

Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings.

This prospective study aimed to evaluate the potential usefulness of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) in the oncological evaluation of patients presenting with inconclusive [18F]FDG PET/CT findings. [68Ga]Ga-DOTA-FAPI-04 was performed in patients presenting with inconclusive [18F]FDG PET/CT findings. Tumour uptake was quantified by the maximum standard uptake value (SUV). Histopathology or follow-up imaging served as the standard for the final diagnosis. A total of 68 patients with inconclusive [18F]FDG PET/CT findings underwent additional [68Ga]Ga-DOTA-FAPI-04 PET/CT. Of them, 18 (26.5%) were for discrimination of mass lesions detected on conventional imaging, 6 (8.8%) for detection of the unknown primary site in biopsy-proven metastatic malignancy, 21 (30.9%) for the staging of cancer, and the other 23 (33.8%) for evaluation of suspected disease recurrence. Most of the primary and metastatic lesions demonstrated higher uptake of [68Ga]Ga-DOTA-FAPI-04 than did [18F]FDG, which resulted in favourable tumour-to-background contrast in various types of cancer. As a result, [68Ga]Ga-DOTA-FAPI-04 PET/CT identified suspicious mass lesions with an accuracy of 12/18 (66.7%), detected the primary site in 4/6 patients (66.7%) with unknown malignancy, upgraded tumour staging in 7/21 patients (33.3%), and detected disease recurrence in 20/23 patients (87.0%). In patients undergoing oncological evaluation with inconclusive [18F]FDG PET/CT findings, [68Ga]Ga-DOTA-FAPI-04 may have a complementary role in discriminating mass lesions on conventional imaging, locating the primary site of unknown malignancy, modifying tumour staging, and detecting suspected disease recurrence. Nevertheless, careful attention should be paid when reading the [68Ga]Ga-DOTA-FAPI-04 PET/CT images in tumours complicated with inflammation.

NGSCUP: Phase II trial of site-specific treatment based on gene expression and mutation profiling by next generation sequencing (NGS) for patients (pts) with cancer of unknown primary site (CUP).

e15577 Background: Although gene profiling is a promising diagnostic technique to determine the tissue of origin for pts with CUP, we reported that site-specific treatment based on gene profiling using microarray did not result in an improvement the survival compared with empirical therapy in the previous randomized phase 2 trial (Hayashi, et. al, JCO 2019). Recently, we have established new integrative diagnostic system combined the gene expression from RNA-sequencing and mutation/copy number variation data from targeted genomic-sequencing using NGS. We have performed a single-arm phase 2 study to assess the efficacy of site-specific therapy determined by this system in previously untreated pts with CUP. Methods: Comprehensive gene profiling was performed by NGS, and an established algorithm was applied to predict tumor origin. Pts with CUP was received site-specific chemotherapy determined by the predicted site. The primary endpoint was one-year survival rate. Results: A total of 111 pts was enrolled and all had sufficient biopsy tissue for gene profiling. Efficacy analysis was performed for 97 pts who received site-specific treatment. Cancer types most commonly predicted were lung (21%), liver (15%), kidney (15%), and colorectal cancer (12%). The one-year survival rate, median overall survival (OS), and progression free survival (PFS) was 53.1% (95%CI, 42.6-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Median OS (15.7 versus 11.0 months, P = .078) and PFS (5.5 versus 2.8 months, P = .019) were better for predicted tumor types categorized as more responsive types than for less responsive ones. Conclusions: Site-specific treatment based on NGS demonstrated promising efficacy. Pts with CUP predicted to have more responsive tumor types had longer survival compared with pts with less responsive tumor types, suggesting that molecular tumor profiling by both DNA and RNA testing contributes to the management of pts with CUP. Clinical trial information: UMIN051180009.

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma.

ObjectiveFirst-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment.Material and methodsThis study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS).ResultsTwenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments.ConclusionLV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

Peritoneal carcinomatosis of unknown primary site, a study of 25 patients over 30 years

IntroductionPeritoneal carcinomatosis may be diagnosed by cytology or CT-guided biopsy, but routine radiologic and endoscopic workup not reveal a primary site. The clinical condition is referred to as peritoneal carcinomatosis of unknown primary site. MethodsOver a 30-year time interval all patients treated with an initial diagnosis of carcinomatosis of unknown primary site were managed on a special clinical pathway. Upper gastrointestinal endoscopy, colonoscopy, and abdominal and pelvic CT were performed. Immunostains suggested a gastrointestinal origin of the carcinomatosis. After these tests, exploratory laparotomy was performed. ResultsTwenty-five patients fulfilled the criteria for peritoneal carcinomatosis of unknown primary site and all 25 of these patients underwent an exploratory laparotomy. Special attention to the anatomic site of the appendix occurred during the exploratory laparotomy. No site within the gastrointestinal tract including a non-cancerous appendix was observed in 9 patients (36%). In 7 patients (28%), the carcinomatosis was so extensive that an adequate exploration to determine a primary site was not possible. In a third group of 9 patients (36%), exploratory laparotomy revealed an occult appendiceal malignancy. ConclusionPeritoneal carcinomatosis of unknown primary site was caused by an occult appendiceal adenocarcinoma in 36% of our patients. This error in diagnosis may lead to suboptimal treatment. Surgical exploration to visualize the anatomic site of the appendix should occur prior to making a definitive diagnosis of peritoneal carcinomatosis of unknown primary site.

Radiotherapeutic management of cervical lymph node metastases from an unknown primary site \u2013 experiences from a large cohort treated with modern radiation techniques

PurposeTo analyze management and outcomes following (chemo)radiation therapy in patients with cervical lymph node metastases from an unknown primary site (CCUP) in a large single-center cohort.MethodsBetween 2008 and 2019, 58 patients with CCUP were treated with (chemo)radiation therapy at the University of Freiburg Medical Center and were included in this analysis. Overall survival (OS), locoregional progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The use of diagnostic procedures and their impact on oncological outcomes was analyzed by Cox regression, and treatment-related toxicities were quantified.ResultsMedian follow-up was 29.9 months (range 4.6–121.9). Twenty-one patients (36.2%) received definitive RT, 35 (60.3%) underwent adjuvant RT, and 2 (3.4%) were treated for oligometastatic disease. Concurrent chemotherapy was prescribed in 40 patients (69.0%). 89.6% of patients completed the prescribed RT, and 65.0% completed the prescribed simultaneous chemotherapy. Locoregional recurrence was observed in 7 patients (12.1%) and distant metastases in 13 cases (22.4%). OS was 81,1, 64.9% and 56,6% after 1, 3 and 5 years, respectively.Univariate analysis of age, gender, extracapsular spread, tumor grading, neck dissection, diagnostic utilization of 18F-fluorodeoxyglucose positron-emission tomography and concomitant chemotherapy showed no effect on OS (p > 0.05 for all), while smoking was significantly associated with decreased survival (p < 0.05). There was a trend towards impaired OS for patients with advanced nodal status (pN3) (p = 0.07). Three patients (5.2%) experienced grade 3 radiation dermatitis, and 12 (22.4%) developed grade 3 and 1 (1.7%) grade 4 mucositis.ConclusionsRT of the panpharynx and cervical lymph nodes with concurrent chemotherapy in case of risk factors demonstrated good locoregional control, but the metachronous occurrence of distant metastases limited survival and must be further addressed.

The role of tumour morphology in assigning HPV status in oropharyngeal squamous cell carcinoma.

There is no consensus on the optimal approach to human papilloma virus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC). Our objective was to classify OPSCC as HPV positive or negative based on (1) morphology alone, (2) p16 status alone, (3) combined morphology and p16 status with additional HPV testing in discordant cases in keeping with 2012 College of American Pathologists (CAP) guidelines (combined approach), and to evaluate and compare survival outcomes. Retrospective review of 168 patients, 146 with OPSCC and 22 with cervical SCC of unknown primary site (SCCUP). Morphology was classified as keratinizing or non-keratinizing, p16 immunohistochemistry (IHC) performed and additional HPV DNA PCR testing undertaken in cases in which morphology and p16 status were discordant. Survival statistics were evaluated and compared for the 3 different approaches to classification. On univariate analysis all 3 classification methods significantly predicted for overall survival (OS). Both p16 status and the combined approach also predicted for disease specific survival (DSS), whereas morphology fell just outside significance (p = 0.06). On multivariate analysis only the combined approach retained significance for both OS and DSS, whilst morphology was also significant for DSS. Our findings confirm that tumour morphology significantly predicts for survival in OPSCC. However, we found combined tumour morphology and p16 IHC, with additional testing for discordant cases to be superior to either morphology or p16 IHC alone. Further study is required to establish the optimal testing method for HPV in OPSCC particularly in low prevalence populations.

Morphometric and immunohistochemical features of TTF-1 positive lung tumors: improvement of approaches to the diagnosis of unknown primary sites metastases

Verification of lung tumors in the practical activity of a pathomorphologist reached a completely different level due to the use of additional highly sensitive diagnostic methods (immunohistochemical (IHC) and cytogenetic studies). Thyroid transcription factor 1 (TTF-1) plays a key role in lung morphogenesis and is expressed in about 90 % of pulmonary small cell carcinomas. The positivity of TTF-1 in pulmonary and extrapulmonary neuroendocrine tumors is actively debated in the literature, therefore, the results of IHС on TTF-1 in metastases from an unknown source should be interpreted carefully and constantly improve differential diagnostic algorithms, expanding IHC panels with organ-specific markers, and focus on additional morphometric indicators research of nuclei of tumor cells.The aim of the work is to investigate the complex of morphological, morphometric, and IHC characteristics of TTF-1 positive lung tumors to improve the diagnostic algorithms for metastases from an unknown primary source.Materials and methods. A retrospective analysis of histological, morphometric and IHC characteristics of the biopsy material TTF-1 of positive lung carcinomas from 36 patients (10 women and 26 men) aged 29 to 81 years (mean 58.03±10.83 years) for the period 2015–2018, taken from the archive of the morphological department of the medical-diagnostic center of LLC “Pharmacies of the Medical Academy” (Ukraine, Dnipro).Results. In the diagnosis of carcinomas of unknown primary localization with suspected lung origin, it is necessary to take into account morphological, morphometric and IHC features together, which is associated with the similarity of metastases of squamous cell carcinomas of the head and neck, mucinous adenocarcinomas of the gastrointestinal tract and neuroendocrine carcinomas from Merkel cells corresponding to the histological forms lung tumors, as well as insufficient sensitivity of the marker TTF-1.Conclusions. Use of the minimum primary (Cytokeratin, Pan AE1 / AE3 (+) / Vimentin (- / +) / CD45 (-) / S100 (- / +)) and secondary (Ck 7 +, Ck 20 -, TTF-1 + ) IHC panels will prove that the phenotype of carcinoma of unknown primary site corresponds to the form of disseminated lung carcinoma, and additional markers Сk HMW, p63, Chromogranin A, Synaptofisin and / or CD56 together with morphometric indices of the nuclei will determine the histological form of lung carcinoma with justification for the use of appropriate therapy

Diagnostic and health service pathways to diagnosis of cancer-registry notified cancer of unknown primary site (CUP).

Cancer of unknown primary (CUP) is a late-stage malignancy with poor prognosis, but we know little about what diagnostic tests and procedures people with CUP receive prior to diagnosis. The purpose of this study was to determine how health service utilisation prior to diagnosis for people with cancer-registry notified CUP differs from those notified with metastatic cancer of known primary. We identified people with a cancer registry notification of CUP (n = 327) from the 45 and Up Study, a prospective cohort of 266,724 people ≥45 years in New South Wales, Australia, matched with up to three controls with a diagnosis of metastatic cancer of known primary (n = 977). Baseline questionnaire data were linked to population health data to identify all health service use, diagnostic tests, and procedures in the month of diagnosis and 3 months prior. We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). After adjusting for age and educational attainment, people with a cancer-registry notified CUP diagnosis were more likely to be an aged care resident (OR = 2.78, 95%CI 1.37-5.63), have an emergency department visit (OR = 1.65, 95%CI 1.23-2.21), serum tumor marker tests (OR = 1.51, 95%CI 1.12-2.04), or a cytology test without immunohistochemistry (OR = 2.01, 95%CI 1.47-2.76), and less likely to have a histopathology test without immunohistochemistry (OR = 0.43, 95%CI 0.31-0.59). Neither general practitioner, specialist, allied health practitioner or nurse consultations, hospitalisations, nor imaging procedures were associated with a CUP diagnosis. The health service and diagnostic pathway to diagnosis differs markedly for people notified with CUP compared to those with metastatic cancer of known primary. While these differences may indicate missed opportunities for earlier detection and appropriate management, for some patients they may be clinically appropriate.

The diagnostic Value of Cadherin 17 & CDX2 Expression as Immunohistochemical Markers in Colorectal Adenocarcinoma

Abstract Background &amp; Objective Colorectal cancer is a major cause of morbidity and mortality throughout the world. In Egypt, it is the seventh commonest cancer representing 3.47% of male cancers and 3% of female cancers. Although the diagnosis of colorectal cancer is straight forward in primary site, yet it may represent a diagnostic problem in metastatic tumour of unknown primary origin. Pathologists are often called upon to suggest a site of origin in patients with metastasis of an unapparent primary tumour site. This is because some specific tumour types may respond well to targeted molecular therapies. Most tumours of unknown primary site are evaluated with immunohistochemical analysis in combination with morphologic assessment and correlation with clinical data. Therefore, establishment of reliable diagnostic markers that confirm or rule out colorectal origin are mandatory especially in adenocarcinomas of unknown primary site which is one of the most clinical problems. The aim of this work is to study the expression of Cadherin 17 &amp; CDX2 in colorectal carcinoma to evaluate their roles when metastatic colorectal carcinoma is suspected in cancer of unknown primary site. Material &amp; Methods This retrospective study included (65) cases of adenocarcinomas: 35 cases of colorectal adenocarcinoma (whether primary or metastatic) and 30 cases of non colorectal adenocarcinoma from other different sites. Our cases were retrieved from the archives of Pathology Department of Ain Shams University Hospitals and Ain-Shams University Specialized Hospital during the period from (2010 to 2015). Immunohistochemical study was performed using monoclonal cadherin 17 &amp; CDX2 antibodies. Results The sensitivity of CDX2 and cadherin 17 were 97.1% and 100% respectively in detecting colonic adenocarcinoma. The specificity of CDX2 was 53.3% while cadherin 17 showed a specificity of 50%. The PPV, NPV and overall accuracy of CDX2 versus cadherin 17 were 70.8%, 94.1% and 76.9% versus 70%, 100% and 76.9% respectively. Conclusion Cadherin 17 is a more sensitive marker than CDX2 in diagnosis of carcinoma of unknown primary site especially when colorectal carcinoma is suspected.

New rising entities in cancer of unknown primary: Is there a real therapeutic benefit?

Cancers of Unknown Primary Site (CUP) account for approximately 1-3 % of all malignant neoplasms. It represents a heterogeneous group of malignancies without a detectable primary and is characterized by aggressive clinical behavior. Patients with CUP are presumably categorized into prognostic subsets according to their clinical and pathological characteristics. The majority of these patients are chemoresistant and treated with empiric chemotherapy regimens which yield limited survival. Recent diagnostic advances have led to the identification of a higher percentage of culprit primaries among which colorectal, lung and renal tumors. The empiric CUP regimens may be suboptimal in these patients which explain in part their poor prognosis. In the absence of prospective randomized studies to prove the benefit of site-specific therapy in these subsets, we reviewed the literature to assess whether CUP with colorectal, lung and renal - profiles should be treated similarly to the correspondent primary tumors.

Costs and Outcomes of Patients Admitted to the Intensive Care Unit With Cancer.

Cancer is associated with significant health-care expenditure, but few studies have examined the cost of patients with cancer in the intensive care unit (ICU). We aimed to describe the costs and outcomes of patients admitted to the ICU with cancer. We conducted a retrospective cohort study of patients admitted between 2011 and 2016 to 2 tertiary-care ICUs. We included patients with a cancer-related most responsible diagnosis using International Classification of Disease, 10th Revision, Canada codes. We compared costs and outcomes of patients having cancer with noncancer controls matched for age, sex, and Elixhauser comorbidity score. We used logistic regression to determine predictors of mortality among patients with cancer. There were 1022 patients with cancer during the study period. Mean age was 63.2 years and 577 (56.5%) were male. Inhospital mortality for all patients with cancer was 24.0%. Total cost per patient was higher for patients with cancer compared to noncancer patients (CAD$57 084 vs CAD$40 730; P < .001) but there were no differences in the cost per day (CAD$2868 vs CAD$2887; P = .76) or ICU cost (CAD$30 495 vs CAD$29 382; P = .42). Among patients with cancer, the cost per day was higher for nonsurvivors (CAD$3477 vs CAD$2677; P < .001). Liver disease (odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.22-7.81), mechanical ventilation (OR: 1.73; 95% CI: 1.25-2.39), hematologic malignancy (OR: 3.88; 95% CI: 2.31-6.54), and unknown primary site (OR: 2.13; 95% CI: 1.36-3.35) were independently associated with mortality in patients with cancer. Patients admitted to the ICU with cancer did not differ in cost per day, ICU cost, or mortality compared to matched noncancer controls. Among patients with cancer, nonsurvivors had significantly higher cost per day compared to survivors. Hematologic and unknown primaries, liver disease, and mechanical ventilation were independently associated with mortality in patients with cancer.

A case of meningeal melanomatosis diagnosed by immunostaining of cerebrospinal fluid

A 49-year-old woman was admitted to our hospital with suspected hypertensive encephalopathy. On the basis of MRI showing leptomeningeal enhancement and Class V cytology of the CSF, she was diagnosed as having leptomeningeal carcinomatosis. Although no primary site was detected, a few melanin granules were observed at the third CSF examination. The atypical cells in the CSF demonstrated immunoreactivity for HMB-45 and S-100, which are specific markers of malignant melanoma. There have been few reports of meningeal melanomatosis in Japan. This case illustrates that immunostaining is diagnostically useful in patients with leptomeningeal carcinomatosis from neoplasms with unknown primary sites.

Cancer of Unknown Primary Site: Real Entity or Misdiagnosed Disease?

Metastasis is a late event in the progression of any tumour. However, invasive cancers are occasionally detected in the form of metastatic lesions without a clearly detectable primary tumour. Cancer of unknown primary site (CUP) is defined as a confirmed metastatic tumour, with unknown primary tumour site, despite the standardized diagnostic approach that includes clinical history, routine laboratory tests, and complete physical examination. Due to the lack of basic research on its primary causes, CUP is appropriately termed an 'orphan' cancer. Nevertheless, CUP accounts for 2-5% of diagnosed malignancies. To date, it is unclear whether CUP is an entity with primary dormancy as its hallmark or an entity with genetic abnormalities that cause it to manifest as a primary metastatic disease. In this review, we discuss different aspects of CUP, including its current diagnostic methods, angiogenesis effectors, relationship with cancer stem cells and current treatments.

Detection of metastatic breast carcinoma cells in a bone marrow sample by flow cytometry: case report

Introduction: Breast cancer is a global public health issue due to its high mortality. Despite the multidisciplinary approaches and strategies to reduce mortality, many women are diagnosed in advanced stages with metastases, compromising the chances of cure. Objective: To report the case of a 28-year-old woman, G3, with a history of postpartum depression, on treatment for post-breastfeeding mastitis, with lumbar pain radiating to the chest and lower limbs for 5 months, progressing to epistaxis, hair loss, lymphadenopathy, dyspnea, lower limb petechiae, weight loss of 20 kg, and bicytopenia in the prior 2 months. She was admitted to the emergency department with fever and night sweats and was diagnosed with metastatic breast cancer based on bone marrow (BM) analysis by flow cytometry (FC). Method: BM biopsy (BMB) was performed and evaluated by FC immunophenotyping using the antibodies anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD56, anti-CD34, anti-CD45, and anti-HER2. The streptavidin-biotin-peroxidase method was adopted for the phenotypic evaluation by immunohistochemistry (IHC). Results: Clinical findings and her history favored the hypothesis of lymphoproliferative neoplasm. BM samples were collected for immunophenotyping and BMB for histological study and IHC. The initial aspirate analysis by FC identified 0.90% of non-hematological cells, with a positive expression for the antibody anti-HER2, suggesting epithelial neoplasm, which directed the investigation toward solid tumor with unknown primary site. The presence of this cellular component guided the IHC panel of BMB. Cells positive for CKPOOL, CK7, E-cadherin, estrogen receptor, progesterone receptor, HER2, GCDFP15, and mammaglobin were identified, indicating immunophenotype of metastatic breast disease in the BM. Later, a nodule was clinically detected in the right breast, showing a pattern consistent with that found in the BM sample, confirming the metastatic breast carcinoma. Conclusions: FC has proven to be a methodology of great clinical importance. Its routine laboratory application in the diagnosis of solid tumors could become a useful tool, providing agility and increasing diagnostic coverage.

Metastatic Poorly Differentiated Carcinoma of Unknown Primary Site

Metastatic Poorly Differentiated Carcinoma of Unknown Primary Site