Unknown Primary Site Research Articles

Frequency of metastasis to the gastrointestinal tract determined by endoscopy in a community-based gastroenterology practice

Metastasis to the gastrointestinal tract is rare. We performed a retrospective analysis to identify patients with metastatic disease to the gastrointestinal tract using two databases containing pathology results from all endoscopic procedures conducted by nearly 200 gastroenterologists in a community setting over a 14-year period. Forty-nine patients were diagnosed with metastasis to the gastrointestinal tract by endoscopy during the study period. Most were women (71%). The most common metastases to the gastrointestinal tract identified by endoscopy were breast cancers (n = 18), followed by melanomas (n = 12), ovarian cancers (n = 7), kidney cancers (n = 5), prostate cancers (n = 2), lung cancer (n = 1), and pancreatic cancer (n = 1). Three patients had unknown primary sites. Among women, the three leading known primary tumor sites were breast, ovary, and melanoma. Among men, the three leading primary tumor sites were melanoma, kidney, and prostate. The stomach was the most common portion of the gastrointestinal tract involved by metastases. Most affected women and were most frequently encountered in the stomach.

Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma.

The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.

A retrospective analysis of pleural effusion specimens based on the newly proposed International System for Reporting Serous Fluid Cytopathology.

Recently, the International System for Reporting Serous Fluid Cytopathology (TIS) has been established, with an aim to standardize reporting and guide clinical decision making. The cytological and clinicopathological data of pleural effusions were retrieved from the pathology database and electronic medical records. All specimens were evaluated and reclassified in accordance with the TIS recommendations. Finally, the risk of malignancy (ROM) and performance parameters were measured. A total of 2454 pleural effusion specimens were included, among which 30 (1.2%), 1670 (68.1%), 151 (6.2%), 54 (2.2%) and 549 (22.4%) patients were classified into non-diagnostic (ND), negative for malignancy (NFM), atypia of undetermined significance (AUS), suspicious for malignancy (SFM) and malignancy (MAL) groups, respectively. The most commonly diagnosed malignancies were lung cancer (48.4%), ovary cancer (10.2%), breast cancer (7.5%), and 21.3% unknown primary site (UPS). Among the 36 UPS patients, the most common site of origin was lung (36.1%), followed by ovary (13.9%) and breast (11.1%) via immunocytochemistry of cell block. The calculated ROM values were 26.7%, 12%, 62.3%, 77.8% and 100% for ND, NFM, AUS, SFM and MAL groups, respectively. When considering MAL as the only positive group, the diagnostic accuracy, sensitivity, specificity, positive and negative predictive values were determined to be 95.2%, 81.9%, 100%, 100% and 93.6%, respectively. The newly proposed TIS is an easy-to-master, user-friendly, and standardized classification system, especially when applying on pleural effusions. An adequate serous sample, application of immunocytochemistry, review of cytomorphological data and past medical history could enhance the accuracy of cytological diagnosis.

Confirmatory germline testing for presumed germline pathogenic variants using tumor-only testing.

e22524 Background: Presumed germline pathogenic variants (PGPVs) can be detected in tumor tissues using comprehensive genomic profiling. Clinicians and patients can decide whether to conduct confirmatory germline testing or not. However, the promoting and obstructive factors for confirmatory germline testing are unclear. Methods: This single institutional retrospective study aimed to identify factors related to confirmatory germline testing in patients with PGPVs. Between April 2015 and April 2019, 270 consecutive patients with cancers of unknown primary site, rare tumors, or solid tumors refractory to standard chemotherapy, who underwent tumor-only comprehensive genomic profiling were reviewed. PGPVs were proposed to be disclosed as variants to the patients by our institutional molecular tumor board. Univariate logistic regression analysis was conducted to investigate the relationship between each patient’s characteristics and confirmatory germline testing. Factors showing a statistical relationship (p < 0.10 in univariate analyses) were included in multivariate logistic regression analysis with a backward selection of variables. Statistical significance was set at p < 0.05. Results: Of the 270 patients who underwent tumor-only comprehensive genomic profiling, 77 possessed PGPVs. The most common PGPVs were TP53 (n = 56), APC (n = 9), PTEN (n = 7), RB1 (n = 6), and BRCA2 (n = 6). Among the 77 patients, only 11 (14.3%) chose to undergo confirmatory germline testing. Multivariate logistic regression analysis revealed that the person disclosing the results (experienced oncologists with knowledge of cancer genome medicine vs. others, odds ratio [OR]: 27.7, 95% confidence interval [CI]: 4.60–167) and study period (OR: 0.110, 95% CI: 0.015–0.787) were independently and significantly associated with confirmatory germline testing. Conclusions: These findings indicate that fostering genomic competency in oncologists and collaborating with genetic experts would facilitate cancer patients and their families to receive genetic medical services in the process of cancer genomic profiling.

Dual tracer hybrid radionuclide imaging of a metastatic gastrointestinal neuroendocrine tumor with unknown primary site using 18F-FDG PET/CT and 99mTc-HYNIC-TOC SPECT/CT (case report and literature review)

Neuroendocrine tumors (NEТ) are a heterogeneous group of neoplasms of various locations originating from the APUD system cells with biologically active properties. Although immunohistochemical assay for Ki-67 has been proved to have prognostic significance in GEP-NENs, pitfalls may lead to misjudgment of the tumor grades, prognosis and during treatment planning due to the presence of cells with varying degrees of differentiation and proliferative activity within a single lesion, as well as the entire neoplastic process. These features can affect the results of imaging and therapy planning.An increase in the number of somatostatin receptors on the surface of membrane cells, as well as an increase in glycolysis may occur in NETs. These phenomena play role when choosing imaging methods, as well as in treatment planning.Combined dual-tracer imaging, specifically PET/CT or SPECT/CT using labeled somatostatin analogues can be used in intermediate assessment of cellular heterogeneity in the entire neoplastic process in NENs and help to minimize diagnostic pitfalls listed above.We present an observation of a patient with metastatic GEP-NEN of unknown primary in which 18F-FDG PET/CT and 99mTc-HYNIC-TOC SPECT/CT were performed for initial staging. In the framework of this, aspects of use of dual-tracer radionuclide imaging in patients with NENs are widely discussed.

Four Cases of Mediastinal Lymph Node Carcinoma of Unknown Primary Site After Chemoradiotherapy with a Long Survival

Four Cases of Mediastinal Lymph Node Carcinoma of Unknown Primary Site After Chemoradiotherapy with a Long Survival

UNKNOWN PRIMARY TUMOR SITES IN SPINAL METASTASIS

ABSTRACT Objective: The goal of the study was to report the prevalence of spinal metastasis with unknown primary tumor, clinical features, treatment results and patient survival. Methods: A retrospective evaluation of 103 patients with spinal metastasis and epidural compression, who underwent surgical treatment between March 2009 and August 2015. The prevalence of metastatic spinal tumor with unknown primary tumor was evaluated, as well clinical features, survival and treatment results. Results: Of 103 patients with spinal metastasis and epidural compression, seven patients (6.8%) with unknown primary tumor site were identified; five (71.4%) male and two (28.6%) female, with ages ranging from 37 to 67 years (50.7 years). The metastasis was located in the thoracic spine in six of the patients (85.7%) and in the cervical spine in one (14.3%). The mean survival time was 44.8 days. Conclusion: Spinal metastasis with unknown primary tumor was found in 6.8% of patients. The prognosis and outcomes were poor, and patients had poor survival rates. Level of evidence III; Experimental study.

Undifferentiated cancer with unknown primary location infiltrating the rectum – a case report

Colorectal cancer (CRC) is the third leading malignancy in men after prostate and lung cancer. Adenocarcinomas account for about 90% of all colorectal cancer cases. Carcinomas of unknown primary site (CUPs) are usually found in patients > 60 years of age. They account for 3% of all malignancies in Poland. We describe a diagnostically challenging case of undifferentiated carcinoma of unknown primary site invading the rectum. Rectal specimens collected during endoscopy and open biopsy, as well as samples collected during laparotomy from the side of the peritoneal cavity did not confirm cancer despite progressing clinical symptoms of an ongoing neoplastic process. Histopathological diagnosis was obtained only with core-needle biopsy of the rectal infiltration and sphincter muscles. The histopathological confirmation of carcinoma invading the sigmoid colon, rectum, anus and the mesorectum described in PET-CT enabled patient qualification for further palliative treatment.

TP53 Mutations as a Driver of Metastasis Signaling in Advanced Cancer Patients.

Simple SummaryThe DNA sequencing of cancer provides information about specific genetic changes that could help with treatment decisions. Tumors from different tissues change over time and acquire new genetic changes particularly with treatment. Our study analyzed the gene changes of 171 advanced cancer patients. We predicted that tumors gain new mutations but that TP53 mutations (guardian of the human genome) are conserved as the tumor progresses from primary to metastatic sites and across tissue types. We analyzed the primary and metastatic site gene changes in 25 tissue types and conducted in-depth analysis of colon and lung cancer sites for substantial changes. TP53 site specific mutations were different across tissue types and suggest different molecular changes. Other genetic changes that occur together with TP53 as drivers collectively alter how cells respond to signals which are important to tumor treatments.Molecular profiling with next generation sequencing (NGS) delivers key information on mutant gene sequences, copy number alterations, gene-fusions, and with immunohistochemistry (IHC), is a valuable tool in clinical decision making for patients entering investigational agent trials. Our objective was to elucidate mutational profiles from primary versus metastatic sites from advanced cancer patients to guide rational therapy. All phase I patients (n = 203) with advanced cancer were profiled by commercially available NGS platforms. The samples were annotated by histology, primary and metastatic site, biopsy site, gene mutations, mutation count/gene, and mutant TP53. A molecular profile of each patient was categorized into common and unique mutations, signaling pathways for each profile and TP53 mutations mapped to 3D-structure of p53 bound to DNA and pre/post therapy molecular response. Of the 171 patients analyzed, 145 had genetic alterations from primary and metastatic sites. The predominant histology was adenocarcinoma followed by squamous cell carcinoma, carcinoma of unknown primary site (CUPS), and melanoma. Of 790 unique mutations, TP53 is the most common followed by APC, KRAS, PIK3CA, ATM, PTEN, NOTCH1, BRCA2, BRAF, KMT2D, LRP1B, and CDKN2A. TP53 was found in most metastatic sites and appears to be a key driver of acquired drug resistance. We highlight examples of acquired mutational profiles pre-/post- targeted therapy in multiple tumor types with a menu of potential targeted agents. Conclusion: The mutational profiling of primary and metastatic lesions in cancer patients provides an opportunity to identify TP53 driver ‘pathways’ that may predict for drug sensitivity/resistance and guide rational drug combinations in clinical trials.

A narrative review of malignant eosinophilic pleural effusion: incidence, etiology and prognostic significance.

Eosinophilic pleural effusion (EPE) is defined as a pleural fluid with an eosinophilic count exceeding 10% and currently considered to be mainly caused by malignancy. However, the incidence, etiology and prognostic significance of malignant eosinophilic pleural effusion (MEPE) have not been studied extensively yet. Thus, the objective of this review was to summarize medical studies regarding MEPE to 2020 throughout an extensive search of PubMed. Overall, MEPE was a disease associated with multiplecytokines-mediated immunity and varied from 4% to 92% of patients who had EPE. The discrepancy of the MEPE prevalence among studies could be explained by the development of diagnostic technology, disparity of study population, or various disease spectrum over time. Data summarized in this review demonstrated that the incidence of malignancy was lower in EPEs than in non-EPEs (29.7% vs. 32.9%). Additionally, MEPE could be a manifestation of a great variety of tumor subtypes, among which lung cancer was the most common cause and accounted for more than 34% of cases. The second common causes were non-Hodgkin lymphoma and metastatic cancers with unknown primary site which were observed in around 5% of cases, respectively. The presence of eosinophils in the pleural effusion may be associated with a positive prognosis of MEPE. Besides, the prognosis of MEPE may be related to the percentage of eosinophils in the pleural fluid. More extensive studies, however, are warranted to validate these findings.

A Stepwise Approach to Identify the Clinical Role of FDG PET-CT in Patients with Suspicious Bone Metastasis from an Unknown Primary Site

Objectives: In patients with suspicious bone metastasis, differential diagnosis and primary lesion identification is very important in optimizing treatment planning. The study was aimed to assign a step-wise approach based on image findings to identify the precise role of PET-CT in these patients.
 Patients and Methods: A total of 74 patients were enrolled with suspicious bone metastasis who underwent PET-CT for the evaluation of primary focus. Patients were classified into four groups with stepwise manners, firstly based on FDG positivity of bone lesions, then on multiplicity of positive bone uptake and finally on presence of extra-skeletal uptake. We analyzed the difference of distribution of follow-up results according to each group. In addition, we also investigated whether PET-CT had a role to guide biopsy sites.
 Results: Except for 7 patients without bone or extra-skeletal uptake, 44 patients were categorized in multiple bone and extra-skeletal uptake group (A), 12 in multiple bone uptake without extra-skeletal uptake group (B), 3 in single bone and extra-skeletal uptake group (C) and 8 in single bone uptake without extra-skeletal uptake group (D). In group A, 42/44 patients had metastatic bone disease; where primary lesion was correlating extra-skeletal uptake in 40 (91.0%) cases. Among the 12 patients of group B, 5 (41.7%) had primary malignant bone disease, 3 (25.0%) had benign bone lesions and 4 (33.3%) had metastatic bone disease but PET-CT failed to indicate the primary site. In group C, PET-CT positive extra-skeletal uptake sites were confirmed as primary lesions in all the 3 patients. Among the 8 patients of group D, 5 (62.5%) were benign bone disease, one (12.5%) was high grade sarcoma and the remaining two (25.0%) were metastatic bone disease where PET-CT failed to identify primary site. Additionally, there was significant (P = 0.0003) difference in prevalence of biopsy sites performed according to the presence of extra-skeletal uptake in PET-CT.
 Conclusion: Clinical impact of PET-CT was different according to groups classified with stepwise manners, which suggested that different strategies should be taken especially when there was not extra-skeletal uptake to optimize management plan. PET-CT also had a significant role in patients with extra-skeletal uptake lesion through guidance of easily approachable biopsy sites.
 Bangladesh J. Nuclear Med. 22(2): 95-102, Jul 2019

Neuroendocrine neoplasms of the biliary tree, liver and pancreas: a pathological approach.

SummaryNeuroendocrine neoplasms of the pancreatobiliary tract and liver are a heterogeneous group that encompass a spectrum of entities with distinct morphological, biological and clinical features. Although in the various anatomical sub-sites of this region they show specific characteristics, these tumors, as a whole, share several etiological and clinical aspects. This review systematically addresses NENs arising in the extrahepatic bile ducts, gallbladder, liver and pancreas, with the principal aim of pinpointing essential diagnostic and classification issues. In addition, the section on hepatic NENs has been expanded to include metastatic disease of unknown primary site.

First person profile: George J. Bosl, MD: Former long-term chair of Memorial Sloan Kettering Cancer Center's Department of Medicine reflects on his multifaceted career.

First person profile: George J. Bosl, MD: Former long-term chair of Memorial Sloan Kettering Cancer Center's Department of Medicine reflects on his multifaceted career.

Technical feasibility of radiomics signature analyses for improving detection of occult tonsillar cancer

Diagnosis of occult palatine tonsil squamous cell carcinoma (SCC) using conventional magnetic resonance imaging (MRI) is difficult in patients with cervical nodal metastasis from an unknown primary site at presentation. We aimed to establish a radiomics approach based on MRI features extracted from the volume of interest in these patients. An Elastic Net model was developed to differentiate between normal palatine tonsils and occult palatine tonsil SCC. The diagnostic performances of the model with radiomics features extracted from T1-weighted image (WI), T2WI, contrast-enhanced T1WI, and an apparent diffusion coefficient (ADC) map had area under the receiver operating characteristic (AUROC) curve values of 0.831, 0.840, 0.781, and 0.807, respectively, for differential diagnosis. The model with features from the ADC alone showed the highest sensitivity of 90.0%, while the model with features from T1WI + T2WI + contrast-enhanced T1WI showed the highest AUROC of 0.853. The added sensitivity of the radiomics feature analysis were 34.6% over that of conventional MRI to detect occult palatine tonsil SCC. Therefore, we concluded that adding radiomics feature analysis to MRI may improve the detection sensitivity for occult palatine tonsil SCC in patients with a cervical nodal metastasis from cancer of an unknown primary site.

Risk factors and predictors for tumor site origin in metastatic adenocarcinoma of unknown primary site.

BackgroundMetastatic adenocarcinoma of unknown primary site (MACUP) is the most common cancer of unknown primary site, and shows worse prognosis. Prediction of its tumor site origin attracts a growing attention. However, the site determined by gene expression profiling does not have a significant impact on the survival. Some other special method might need to be found out.MethodsWe reviewed 1011 MACUP patients diagnosed by pathological examination and immunohistochemistry based on the Surveillance, Epidemiology, and End Results (SEER) database during 2010–2016. Kaplan–Meier curves and Cox proportional hazard model were analyzed to compare the survival. Logistic regression models and relevant nomograms were performed to predicting the probability of the primary site which including digestive system, respiratory system, and female breast. The validation and clinical utility of models were measured with relevant statistical approaches.ResultsAbout 324 (32.1%), 299 (29.6%), and 203 (20.1%) of MACUP patients were identified as the primary sites of digestive system, respiratory system, and female breast, respectively. Patients derived from digestive system and respiratory system showed poorer survival than these with other sites. Digestive system was significantly associated with liver (Odds ratio =13.21 [95% confidence interval =8.48–21.02]) or lung (2.36 [1.40–3.97]) metastasis, while respiratory system was linked to brain (11.68 [6.68–21.26]) or lymph node (3.39 [2.26–5.13]) metastasis. Patients identified as female breast were prone to occur bone metastasis (5.85 [3.68–9.45]). Logistic regression nomograms were developed to help clinicians intuitively predict the probabilities of tumor site origin with 0.867, 0.824, and 0.753 of the C‐index, respectively. Decision curve analysis and clinical impact curves both revealed the clinical effectiveness.ConclusionsWe profiled different tumor site origin of MACUP patients and established prediction models. These features might be significant for clinicians to improve the probabilities of predicting the primary sites, and to decide subsequent treatment strategy.

Clinical analysis of patients suspected of cervical lymph node metastases from an unknown primary site

Clinical analysis of patients suspected of cervical lymph node metastases from an unknown primary site

TRANSCUP: A Scalable Workflow for Predicting Cancer of Unknown Primary Based on Next-Generation Transcriptome Profiling

Abstract Cancer of unknown primary site (CUP) accounts for 5% of all cancer diagnoses. These patients may benefit from more precise treatment when primary cancer site was identified. Advances in high-throughput sequencing have enabled cost-effective sequencing the transcriptome for clinical application. Here, I present a free, scalable and extendable software for CUP predication called TRANSCUP, which enables (1) Raw data processing, (2) Read mapping, (3) Quality re-port, (4) Gene expression quantification, (5) Random forest machine learning model building for cancer type classification. TRANSCUP achieved high accuracy, sensitivity and specificity for tumor type classification based on external RNA-seq datasets. It has potential for broad clinical application for solving the CUP problem. TRANSCUP is open-source and freely available at https://github.com/plsysu/TRANSCUP

Melanoma of unknown primary: New perspectives for an old story.

Melanoma of unknown primary site (MUP) comprises 3-4 % of all melanomas. It mostly presents in lymph nodes (LNs), followed by subcutaneous sites, and visceral organs; nevertheless, there is a trend of increase in the relative incidence of visceral counterpart in recent years. Spontaneous regression of the primary lesion is a well-established theory, based on the evidence that melanoma can undergo regression at the primary site. MUP and stage-matched melanoma of known primary site (MKP) share similar prognostic factors. The survival rate of patients with MUP has been compared to those with stage-matched MKP. Multiple studies conducted before the era of novel therapy with immune checkpoint or BRAF/MEK inhibitors found improved survival in favor of MUP, whereas others reported equivalent or poorer outcomes. Here, we discuss the genetic and molecular features, epidemiology, diagnosis, prognostic factors, survival, and treatment of MUP in comparison with MKP, in the pre- and post-novel therapy era.

Liječenje tumora nepoznatog primarnog sijela

Cancer of an unknown primary site is most commonly an aggressive metastatic tumor with a median patient survival of 6 to 9 months. Histologically, it is predominantly adenocarcinoma, and if the primary site is subsequently diagnosed, it is usually the pancreas or lung. Biopsy should be performed whenever possible to classify a tumor of unknown primary origin into one of the following entities: adenocarcinoma, poorly differentiated carcinoma with characteristics similar to adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, poorly differentiated neoplasm. After determining the primary tumor type, the subtype is determined by immunohistochemical staining. In oligometastatic disease, there is a possibility of surgical treatment. Radiotherapy is used as a part of combined modality treatment. Most patients with cancer of unknown primary have an unfavorable prognosis despite multiple chemotherapy agents, and no protocol can be recommended as standard therapy.

Malignant pleural effusions with unknown primary sites: A 6 years cytological study

Introduction: Malignant pleural effusion is an important complication found in patients of advanced cancers and lead on to exudative effusions. Not much data is available regarding malignant pleural effusions with unknown primary sites so we had conducted a retrospective study to highlights the primary sites in cases of malignant pleural effusions. Materials and Methods: The present study was conducted at a tertiary care centre at Ludhiana, Punjab. Retrospective analysis of case records of 104 patients, diagnosed as malignant pleural effusions on cell cytology out of 2948 cases of pleural fluids during a 6 years period (2012 to 2017) was done and the results were analysed to assess the causes and various primary sites of malignant pleural effusion. Results and Conclusion: A total of 104 pleural fluid samples were found to be positive for malignancy out of 2948 cases of pleural fluids during the study period time. Lung carcinoma was found to be the most common cause of malignant pleural effusion. On morphology, adenocarcinoma was the most common type of cytological diagnosis in all pleural effusions. Unknown primary malignancies presented as pleural effusions in many cases with no specific signs & symptoms. Cytological study can reveal the morphological diagnosis & clinch the primary site of origin in more than 50% of cases. Cytological analysis of pleural fluid should be the initial diagnostic approach to diagnose malignant pleural effusions and tapped effusions must always be sent for cytological study. Keywords: Effusion, Lung, Malignancy, Primary site.