Carcinoma Of Unknown Primary Site Research Articles

A multi-centre, single arm, phase 2 trial of pembrolizumab in treatment-naïve patients with carcinoma of unknown primary site.

2659 Background: Cancer of unknown primary (CUP) represents a heterogeneous group of cancers that present with metastatic epithelial disease with no identifiable primary lesion at the time of diagnosis. Patients with poor prognostic features have limited effective systemic therapy options. Researchers hypothesize that these primary lesions are occult, in part, due to anti-cancer immune surveillance. We hypothesize, pembrolizumab will have activity in this setting. Methods: This single arm phase 2 study evaluated the use of pembrolizumab in treatment naïve patients with poor prognosis CUP. Patients ≥18 years of age with ECOG PS 0-1 and histologically proven, measurable metastatic carcinoma with no primary site identified were eligible. Pembrolizumab was administered at 200 mg intravenously every 3-weeks for up to 24 months. The primary endpoint was safety and objective response rate (ORR) per RECIST 1.1. Secondary objectives included progression free survival (PFS) and overall survival (OS). The study used a Simon’s two stage design based on a one-sided test with a type 1 error rate of 0.1, null hypothesis for ORR ≤ 20% yielding a power of 0.8 with an alternate hypothesis of ≥40%. The null hypothesis will be rejected if 8 or more responses are observed in 25 patients. Mismatch repair (MMR) and microsatellite instability (MSI) testing was not mandatory for patients. Results: There were 27 evaluable and 6 unevaluable (no response assessment, included in adverse event analysis) patients. The median age was 64 (range 21-80) and the majority were male (57.6%) and ECOG 1 (84.8%). Four patients experienced grade 3 treatment related adverse events (pain, anorexia, fatigue, confusion, and anemia). There were no treatment related deaths or new signals of toxicity. Of the evaluable patients, the ORR was 18.5% (4 partial responses and 1 complete response), disease control rate was 51.9% (9 stable disease) and thus the null hypothesis could not be rejected. For evaluable patients, the median PFS and OS were 2.56 (95% CI 2.10 – 7.46) and 9.79 (95% CI 3.84 – 16.03) months respectively. The one patient who developed a CR had MMR deficiency and has completed 2 years of therapy. Of the 4 patients with a partial response, one had an MMR proficient tumour, while the remaining 3 had unknown MMR status. Conclusions: Although not meeting the primary endpoint, pembrolizumab has some activity in CUP patients. Patients with CUP should be screened for MMR or MSI. Future studies should evaluate combination therapies with the addition of pembrolizumab. Clinical trial information: NCT03391973 .

SMARC deficient carcinoma of unknown primary site: a case report

The Switch/Sucrose Non-Fermentable (SWI/SNF) protein complex functions as a tumour suppressor through chromatin remodelling. Mutations in genes that encode complex subunits have been identified in a rare subset of aggressive poorly differentiated malignancies across anatomical sites, including thorax, gastrointestinal, genitourinary and sinonasal tracts.1,2 The mutations are independent predictors of poor outcome. Cases presenting as isolated lymphadenopathy are uncommon.3

Algorithmic approach of immunohistochemistry in metastatic carcinoma of unknown primary site

Cancers of unknown primary site (CUPs) are histologically confirmed metastatic carcinoma for which primary site cannot be identified after standard diagnostic approach. It comprises 3-4% of all malignant neoplasms. The broad tumour type for CUPs is carcinoma. Metastatic tumours are more difficult to classify than primaries by Immunohistochemistry (IHC). Integration of morphology & IHC is the gold standard at diagnosing CUP. It is important to be aware of possible pitfalls of IHC and pay attention to correct interpretation. One should have a working algorithmic approach to identifying and classifying CUPs.

A retrospective analysis of the concordance of diagnosis predicted by cancer type ID test with pathological or clinical diagnosis with incorporation of treatment response data.

e18684 Background: Carcinoma of unknown primary site (CUP) is a clinical conundrum, where there is metastatic cancer in multiple organs, but the original site of the cancer cannot be determined either by clinical information, or by pathological specification. In most scenarios, clinical and pathological information may narrow down to 2 or 3 most likely primaries; while in some cases, the pathological diagnosis and the clinical picture may not be in concordance. Cancer type ID test, using a panel of 92 genes detectable by RT-PCR test, and bio-informative algorithm, may provide independent information on the cancer of origin. Incorporating this result, as well as the treatment information, one may be able to get closer to the true site of origin for CUP cases. Methods: Patients who have had a Cancer type ID test (ID test) performed and had received systemic treatment were eligible for this study. We analyzed the concordance of ID result of major probability (> 90% probability) with pathology diagnosis, the concordance of ID result of minor probability (6% probability or “cannot exclude with < 5% probability” with pathology diagnosis, and the concordance of ID result of major probability with final clinical diagnosis (incorporating treatment response data, tumor next gene sequencing data, and genetic test data). We also divided cases into groups of differentiation between 2-3 possible primaries, or true CUPs (as shown in the table below). Results: 26 patients were identified. There were 9 males and 17 females. The median age was 65 years old (ranger 37-92). The final clinical diagnoses were GI (upper and lower intestinal) (n = 6), pancreatic (n = 3), cervical (n = 2), lung adeno (n = 2), lung carcinoid (n = 1), sarcoma (n = 1), GYN (n = 2), Head neck (n = 1) and breast (n = 1). 7 cases remained as CUP. Conclusions: Cancer type ID test, with a combination of 90% probability, the 6% probability as well as the “cannot exclude with a less than 5% probability”, may reach 92% concordance with pathological diagnosis. It has the highest prediction in differentiation of 2-3 primaries, especially when one primary involves pancreas. However, the concordance between the clinical diagnosis and the diagnosis rendered by the ID test major prediction is not optimal, and will need further improvement.[Table: see text]

Carcinoma of Unknown Primary Site With Papillary Renal Cell Carcinoma Features and Without a Kidney Primary Lesion: A Diagnostic and Therapeutic Challenge

Renal cell carcinoma is well-known for its metastatic potential and a quarter of the patients present with advanced disease. However, the occurrence of a metastatic renal cell carcinoma without a kidney primary lesion is very uncommon. Herein, we present a case of a 46-year-old male patient with neck lymph node metastasis of a carcinoma of unknown primary site with papillary renal cell carcinoma features without a primary renal mass, highlighting the diagnostic and therapeutic challenges of this rare neoplasm.

Pan-Cancer DNA Methylation Analysis and Tumor Origin Identification of Carcinoma of Unknown Primary Site Based on Multi-Omics.

The metastatic cancer of unknown primary (CUP) sites remains a leading cause of cancer death with few therapeutic options. The aberrant DNA methylation (DNAm) is the most important risk factor for cancer, which has certain tissue specificity. However, how DNAm alterations in tumors differ among the regulatory network of multi-omics remains largely unexplored. Therefore, there is room for improvement in our accuracy in the prediction of tumor origin sites and a need for better understanding of the underlying mechanisms. In our study, an integrative analysis based on multi-omics data and molecular regulatory network uncovered genome-wide methylation mechanism and identified 23 epi-driver genes. Apart from the promoter region, we also found that the aberrant methylation within the gene body or intergenic region was significantly associated with gene expression. Significant enrichment analysis of the epi-driver genes indicated that these genes were highly related to cellular mechanisms of tumorigenesis, including T-cell differentiation, cell proliferation, and signal transduction. Based on the ensemble algorithm, six CpG sites located in five epi-driver genes were selected to construct a tissue-specific classifier with a better accuracy (>95%) using TCGA datasets. In the independent datasets and the metastatic cancer datasets from GEO, the accuracy of distinguishing tumor subtypes or original sites was more than 90%, showing better robustness and stability. In summary, the integration analysis of large-scale omics data revealed complex regulation of DNAm across various cancer types and identified the epi-driver genes participating in tumorigenesis. Based on the aberrant methylation status located in epi-driver genes, a classifier that provided the highest accuracy in tracing back to the primary sites of metastatic cancer was established. Our study provides a comprehensive and multi-omics view of DNAm-associated changes across cancer types and has potential for clinical application.

Sparing the Larynx and Hypopharynx With Radiotherapy for Squamous Cell Carcinoma of Unknown Primary Site and Predominant Adenopathy in Level IIA

There is controversy about the need to target the mucosa of the larynx and hypopharynx during radiotherapy (RT) for squamous cell carcinoma of unknown primary site (SCCA-UP). By 1997, the policy in our department was to target only the oropharynx and nasopharynx in patients with SCCA-UP metastatic to the level II cervical nodes. The purpose of this study is to report the rate of cancer recurrence in the larynx or hypopharynx using an approach that excluded these areas from the RT target volumes.We reviewed the medical records of patients who met the following inclusion criteria: received RT in our department for SCCA-UP between January 1, 1997, and December 31, 2019; no history of surgery that could disrupt the cervical lymphatics; predominant adenopathy in level IIA; and neck stage N1-2c. We excluded N3 because the incidental dose to the larynx and hypopharynx is usually high in patients with a > 6-cm nodal conglomerate. We calculated the following from the date of the last RT fraction: mucosal control to the date of first recurrence in a mucosal site in the head and neck; regional control with or without distant control to the date of first recurrence in ipsilateral or contralateral neck nodes with or without distant disease; distant control to the date of first documented metastatic lesion most likely originating from SCCA-UP; relapse-free survival to the date of recurrent disease at any site or death; cause-specific survival to the date of death due to SCCA-UP; and overall survival to the date of death from any cause.The study population included 50 patients with a median follow-up after RT of 7.1 years. No patient developed recurrent cancer in a mucosal site (0/50), 2% (1/50) developed a neck recurrence in a high-dose area with synchronous distant metastases, and 2% (1/50) developed distant metastases with no evidence of local or regional recurrence. At most recent follow-up, 70% (35/50) of patients were alive without evidence of recurrent SCCA-UP (NED), 4% (2/50) died of recurrent cancer, 22% (11/50) died of intercurrent disease (DID), and 4% (2/50) died of unknown causes (unknown).When delivering RT for SCCA-UP metastatic predominantly to level IIA, it is not necessary to target the mucosa of the larynx or hypopharynx. The extent to which the incidental RT dose to these areas contributes to cancer control is not evaluated in this study.

Postmortem diagnosis of pulmonary tumor thrombotic microangiopathy with rapid exacerbation in a patient with gastric cancer: a case report

BackgroundPulmonary tumor thrombotic microangiopathy (PTTM) is a condition that involves the development of pulmonary hypertension due to the presence of microscopic tumor emboli of the peripheral pulmonary arteries. Here, we report a case of rapidly exacerbating PTTM associated with gastric cancer that was identified postmortem through pathological autopsy.Case presentationA 52-year-old Asian woman who experienced anterior chest pain while coughing visited the orthopedic department of the Gifu University Hospital. She was diagnosed as having multiple osteolytic bone metastases throughout her body and was subsequently scheduled to undergo combined positron emission tomography and computed tomography (CT) to search for a primary lesion. However, 4 days after her visit to the orthopedic department, she was unable to stand up and thus visited the emergency department. At the time of admission, physical examination results revealed that she had a percutaneous oxygen saturation level of 90% (on room air) and cyanosis and that she was in a state of hemodynamic shock. Laboratory test results revealed elevated levels of fibrin degradation products and D-dimer in her blood. Chest CT results were normal. She was admitted to the hospital’s general ward for follow-up but soon entered a gradually worsening state of shock and respiratory failure. Electrocardiography revealed findings associated with right heart strain; however, contrast-enhanced CT did not reveal the presence of pulmonary embolism. She was admitted to the intensive care unit and was treated for pulmonary hypertension; however, 45 h after her arrival at the hospital, she died of respiratory failure. A pathological autopsy revealed the presence of gastric cancer, tumor microemboli, and fibrous intimal thickening of the peripheral arteries of both lungs; thus, a diagnosis of PTTM was made.ConclusionsIn patients with carcinoma of unknown primary site and pulmonary hypertension with pulmonary embolism ruled out by CT, emergency physicians and intensivists must consider the possibility of PTTM, which represents an oncologic emergency, and initiate chemotherapy administration as soon as possible.

Sparing the Larynx and Hypopharynx With Radiation Therapy for Squamous Cell Carcinoma of Unknown Primary Site and Predominant Adenopathy in Level IIA

PurposeThere is controversy about the need to target the mucosa of the larynx and hypopharynx during radiation therapy (RT) for squamous cell carcinoma of an unknown primary site (SCCA-UP). By 1997, the policy in our department was to target only the oropharynx and nasopharynx in patients with SCCA-UP metastatic to the level II cervical nodes. The purpose of this study was to report the rate of cancer recurrence in the larynx or hypopharynx using an approach that excluded these areas from the RT target volumes. Methods and MaterialsThe inclusion criteria for this study were RT in our department for SCCA-UP between January 1, 1997, and December 31, 2019; no history of surgery that could disrupt the cervical lymphatics; predominant adenopathy in level IIA; and neck stage N1-2c. We excluded N3 because the incidental dose to the larynx and hypopharynx is usually high in patients with a >6-cm nodal conglomerate. ResultsThe study population was comprised of 50 patients with a median follow-up after RT of 7.1 years. No patient developed recurrent cancer in a mucosal site (0/50), 2% (1/50) developed a neck recurrence in a high-dose area with synchronous distant metastases, and 2% (1/50) developed distant metastases with no evidence of local or regional recurrence. ConclusionsWhen delivering RT for SCCA-UP metastatic predominantly to level IIA, it is not necessary to target the mucosa of the larynx or hypopharynx. The extent to which the incidental RT dose to these areas contributes to cancer control is not evaluated in this study.

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

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.

Narrative review on serous primary peritoneal carcinoma of unknown primary site: four questions to be answered.

Serous peritoneal papillary carcinoma (SPPC) represents a particular cancer of unknown primary (CUP) entity that arises in the peritoneal surface lining the abdomen and pelvis without a discriminative primary tumor site. In this review, we discuss the validity of SPPC as a distinct entity. Clinically, patients with SPPC are older, have higher parity and later menarche, are more often obese and probably have poorer survival compared to those with primary ovarian cancer. Pathologically, SPPC is more anaplastic and multifocal, unlike primary ovarian cancer which is commonly unifocal. Biologically, it presents a higher expression of proliferative signals and similar cell cycle and DNA repair protein expression. These differences hint towards SPPC and primary ovarian cancer being as a spectrum of disease. Patients with SPPC are traditionally managed similarly to stage III–IV ovarian cancer. The recommended approach integrates aggressive cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy to remove the macroscopic tumor, eradicate the microscopic residual disease, and control the microscopic metastasis. However, the available evidence lacks proper randomized or prospective studies on SPPC and is limited to retrospective series. The diligent identification of SPPC is warranted to design specific clinical trials that eventually evaluate the impact of the new therapeutics on this distinct entity.

Metastatic renal cell carcinoma of unknown primary site. Clinical follow-up

Renal cell cancer metastases without evidence of a primary tumor are extremely rare. These variants are usually showed as a spontaneous description of single clinical cases.
 Aim.This contribution is a clinical follow-up of synchronous renal cell cancer metastases of unknown primary site.
 Results.A 52-year-old patient U. with a history of increased blood pressure, up to 170/100 mmHg for the last 5 years, who had undergone many instrumental examinations, including ultrasound examination, because of this disease. The computed tomography of the abdomen showed a 4975 mm heterogeneous tumor in the right adrenal gland in October 2017. The combined positron emission and X-ray computed tomography showed a 795441 mm mass in the right adrenal gland, associated with elevated fluorodeoxyglucose metabolic activity SUVmax 7.25. Focal accumulation of the radiopharmaceutical SUVmax 4.31 in a 171124 mm mass was detected in the space of bifurcation in the mediastinum. The lytic lesion (1015 mm) was found in right superior L3 articular process. The patient underwent retroperitoneoscopic adrenalectomy and thoracoscopic removal of mediastinal tumor in November 2017 because of the oligometastatic nature of the process. The histological study identified clear-cell carcinoma with areas of papillary structure in the right adrenal gland. The immunohistochemical study showed carcinoma cells intensively expressing CD10, and some other cells RCC. The immune phenotype of the tumor was identified as clear-cell renal cell carcinoma. The immunohistological and immunohistochemical analysis reviled the metastases of the same variant of renal cell carcinoma in one of 9 lymph nodes. The patient was treated with pazopanib. The primary renal tumor was not detected during the dynamic observation, including the application of annual combined positron emission and X-ray computed tomography. The patient is alive without disease progression with a follow-up of 32 months.
 Conclusion.Metastases of clear-cell renal cell carcinoma, including adrenal gland, without evidence of a primary site are extremely rare. The main method of treatment is a combination of surgery and targeted therapy, providing long-term local control of the course of the disease.

The Diagnostic Value of Cadherin 17 and CDX2 Expression as Immunohistochemical Markers in Colorectal Adenocarcinoma.

Colorectal cancer is a major cause of morbidity and mortality throughout the world. Although the diagnosis of colorectal cancer is straightforward in primary site, yet it may represent a diagnostic problem in metastatic tumor of unknown primary origin. Hence, immunohistochemical analysis in combination with morphologic assessment and correlation with clinical data becomes crucial, because it is important to specify the primary site of metastasis since some specific tumor types may respond well to targeted molecular therapies. Therefore, establishment of reliable diagnostic markers that confirm or rule out colorectal origin is mandatory. To study the expression of cadherin 17 and CDX2 in colorectal carcinoma and to evaluate their diagnostic roles in identifying metastatic colonic from non-colonic adenocarcinomas in cancer of unknown primary site. This retrospective study included 65 cases of adenocarcinomas: 35 cases of colorectal adenocarcinoma (primary or metastatic) and 30 cases of non-colorectal adenocarcinoma. They were retrieved from the archives of Pathology Department of Ain Shams University and Ain Shams University Specialized Hospitals during the period from 2010 to 2015. Immunohistochemical study was performed using cadherin 17 and CDX2 antibodies. The sensitivity and specificity of CDX2 and cadherin 17 are 97.1% and 53.3% and 100% and 50% in detecting colonic adenocarcinoma respectively. 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. Cadherin 17 is a more sensitive marker than CDX2 in diagnosis of carcinoma of unknown primary site especially when colorectal carcinoma is suspected.

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.

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.

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

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

Abstract Background & 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 & CDX2 in colorectal carcinoma to evaluate their roles when metastatic colorectal carcinoma is suspected in cancer of unknown primary site. Material & 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 & 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.

Cervical Carcinoma of Unknown Primary Site

Cervical carcinoma of unknown primary site is a condition characterized by the presence of a metastatic lymph node neck mass in the absence of the primary tumor, despite extensive diagnostic procedures. This condition affects more often male patients with a history of tobacco and alcohol abuse or human papilloma virus (HPV) or Epstein-Barr virus (EBV) chronic infection. The detection of the primary tumor and identification of the histopathological type have a key role in the management of patients with unknown primary tumors. Treatment is multimodal, including surgery, radiotherapy and chemotherapy.