Materiały źródłowe

• #1 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  Cancer of unknown primary (CUP) affects a small percentage of the general population. […] The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. […] Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. […] Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. […] CUP can be viewed as an enigmatic cancer, as the accuracy of the diagnosis and the efficacy of the treatment are questioned. […] CUP has been hypothesised to possess a genetic signature that is specific for its primary site and a second genetic signature that is primary-independent, pro-metastatic and possibly CUP-specific, which differentiates the known and unknown primary tumours.

• #2 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. […] Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. […] According to current understanding, the process of tumorigenesis involves the consecutive sequence of clonal proliferation, invasion and intravasation of cancer cells from the primary tumour, dissemination through the circulation, extravasation in different organs and colonisation at metastatic sites.

• #3

  http://waocp.com/journal/index.php/apjcc/article/view/855

  Cancer of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary. CUP has been reported to comprise approximately 2% to 5% of all cancer cases. […] Carcinoma of unknown primary origin (CUP) is a diverse group of cancers that is defined by the presence of metastatic disease (biopsy proven) with no identified primary Tumour after comprehensive workup. […] The overall prognosis of CUP patients is generally very poor with a median survival of 4-12 months. It has been reported that around 50% of patients alive at 1 year and 10% at 5 years from diagnosis. […] Patients with unknown primary must be subjected to all basic investigations that would lead to better management and early treatment consequently better survival of these patients.

• #4 Carcinoma of Unknown Primary Origin

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2631214/

  Carcinoma of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. […] Whether CUP is a distinct molecular genotype-phenotype relative to metastases of known cancers is unknown. However, use of a robust immunohistochemical panel and emerging molecular data may permit development of a tailored treatment algorithm for CUP patients that will include appropriate use of targeted agents. […] The roles of chromosomal and molecular abnormalities in CUP have been evaluated in several studies, but to date no CUP characteristics have been identified that are unique relative to those of metastases from known primary tumors. […] It has been theorized that in CUP, the angiogenic incompetence of the primary tumor leads to marked apoptosis and cell turnover, resulting in a cancer that acquires a metastatic phenotype; however, this theory cannot be clinically tested. […] Whether CUP has a molecular genotype-phenotype that is distinct from metastases of known primary tumors remains to be elucidated. The identification of specific CUP-related molecular and biochemical targets may help us identify appropriate targeted agents for individual patients with this disease.

• #5 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  Cancer of unknown primary (CUP) affects a small percentage of the general population. […] The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. […] Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. […] Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. […] CUP can be viewed as an enigmatic cancer, as the accuracy of the diagnosis and the efficacy of the treatment are questioned. […] CUP has been hypothesised to possess a genetic signature that is specific for its primary site and a second genetic signature that is primary-independent, pro-metastatic and possibly CUP-specific, which differentiates the known and unknown primary tumours.

• #6 Metastatic Cancer With Unknown Primary Site: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/280505-overview

  In metastatic cancer, the primary site of the cancer usually dictates the treatment, expected outcome, and overall prognosis. Consequently, in patients who present with metastatic cancer without a known primary site, the search for the primary site has high priority. […] Two main hypotheses have been proposed to explain metastatic cancer with an unknown primary (CUP). One is that a single cell escapes the controls of normal cell replication, forms a tumor at the site of origin, and the tumor cells ultimately metastasize to other organs, but the original tumor is too small to be detected at the time of metastasis. […] The second hypothesis, termed true CUP or genuine CUP, is that the primary lesion undergoes early regression while the metastases evolve independently, under the selection pressure of the immune system and their microenvironment. This process results in heterogeneous and genetically diverse tumors that are aggressive and resistant to therapy. Thus, regardless of their cell of origin, CUPs share similarities and can be considered a specific entity.

• #7 Cancer of unknown primary site in the mandibular region: A case report

  https://www.spandidos-publications.com/10.3892/ol.2023.13796

  Cancer of unknown primary site (CUP) is a rare heterogeneous clinical syndrome of metastatic cancer for which the primary site is difficult to determine. The pathogenesis of CUP remains unclear. […] There are two hypotheses to explain the origins of CUP: i) A small, dormant or degenerative undetectable primary tumor means that a distinct primary lesion is the source; and ii) no primary tumor exists and the CUP is independent of a primary tumor mass and biologically different from other metastatic tumors. […] At the time of CUP diagnosis, sufficient tissue for immunohistochemical examination is desirable, but sometimes unavailable, as with the present case study. Molecular tumor profiling (MTP) complements standard pathological assessment to allow determination of CUP tissue origin and is especially valuable when IHC produces uncertain results.

• #8 Metastatic Cancer With Unknown Primary Site: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/280505-overview

  In metastatic cancer, the primary site of the cancer usually dictates the treatment, expected outcome, and overall prognosis. Consequently, in patients who present with metastatic cancer without a known primary site, the search for the primary site has high priority. […] Two main hypotheses have been proposed to explain metastatic cancer with an unknown primary (CUP). One is that a single cell escapes the controls of normal cell replication, forms a tumor at the site of origin, and the tumor cells ultimately metastasize to other organs, but the original tumor is too small to be detected at the time of metastasis. […] The second hypothesis, termed true CUP or genuine CUP, is that the primary lesion undergoes early regression while the metastases evolve independently, under the selection pressure of the immune system and their microenvironment. This process results in heterogeneous and genetically diverse tumors that are aggressive and resistant to therapy. Thus, regardless of their cell of origin, CUPs share similarities and can be considered a specific entity.

• #9 Carcinoma of unknown primary – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/carcinoma-unknown-primary/symptoms-causes/syc-20370683

  Carcinoma of unknown primary is a diagnosis healthcare professionals give when they can’t find where a cancer started. A carcinoma of unknown primary is an advanced cancer that has spread in the body. […] In carcinoma of unknown primary, healthcare professionals find the metastatic cancer. But they can’t find the primary cancer. Carcinoma of unknown primary also is called occult primary cancer. […] The cause of carcinoma of unknown primary often isn’t known. Healthcare professionals use this diagnosis when they find signs of cancer that has spread but can’t find where the cancer started. The place where a cancer started growing is called the primary cancer. […] Carcinoma of unknown primary can happen if: The primary cancer is too small to detect with imaging tests. The primary cancer was killed by the body’s immune system. The primary cancer was removed in an operation for another condition.

• #10 Metastatic Cancer With Unknown Primary Site: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/280505-overview

  In metastatic cancer, the primary site of the cancer usually dictates the treatment, expected outcome, and overall prognosis. Consequently, in patients who present with metastatic cancer without a known primary site, the search for the primary site has high priority. […] Two main hypotheses have been proposed to explain metastatic cancer with an unknown primary (CUP). One is that a single cell escapes the controls of normal cell replication, forms a tumor at the site of origin, and the tumor cells ultimately metastasize to other organs, but the original tumor is too small to be detected at the time of metastasis. […] The second hypothesis, termed true CUP or genuine CUP, is that the primary lesion undergoes early regression while the metastases evolve independently, under the selection pressure of the immune system and their microenvironment. This process results in heterogeneous and genetically diverse tumors that are aggressive and resistant to therapy. Thus, regardless of their cell of origin, CUPs share similarities and can be considered a specific entity.

• #11 Carcinoma of unknown primary – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/carcinoma-unknown-primary/symptoms-causes/syc-20370683

  Carcinoma of unknown primary is a diagnosis healthcare professionals give when they can’t find where a cancer started. A carcinoma of unknown primary is an advanced cancer that has spread in the body. […] In carcinoma of unknown primary, healthcare professionals find the metastatic cancer. But they can’t find the primary cancer. Carcinoma of unknown primary also is called occult primary cancer. […] The cause of carcinoma of unknown primary often isn’t known. Healthcare professionals use this diagnosis when they find signs of cancer that has spread but can’t find where the cancer started. The place where a cancer started growing is called the primary cancer. […] Carcinoma of unknown primary can happen if: The primary cancer is too small to detect with imaging tests. The primary cancer was killed by the body’s immune system. The primary cancer was removed in an operation for another condition.

• #12 Cancer of unknown primary origin – Wikipedia

  https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin

  Cancer of unknown primary source is not a single type of cancer, although researchers have attempted to find a common characteristic that explains why a cancer might spread very early without causing symptoms at the site of origin. […] It is generally accepted that cancer of unknown primary site exists because the primary tumor is not identified due to clinical or technological inefficiencies, or because the primary tumor regresses or stays dormant after spreading the cancer cells that generate the metastases. […] Because stem cells have a natural ability to migrate and also play a key role in cancer development, it has been proposed that a cancer of unknown primary site may form when deregulated, premalignant or cancerous stem cells migrate away from their natural tissue and give rise to a cancer in the new site before or without generating a tumor in their original tissue. […] Forming a tumor in a tissue is not a prerequisite for stem cells to move away from that tissue. […] However, stem cells can also migrate away from their natural tissue without generating a cancer there. […] This view of CUP may provide relief to health professionals and patients.

• #13 CUP Syndrome (Cancer of Unknown Primary) | Medically Roche

  https://medically.roche.com/global/en/microsites/about-cup-syndrome/cup-syndrome.html

  CUP syndrome (cancer of unknown primary) is defined as a histologically and clinically verified cancer for which only metastases can be found at the time of diagnosis, but no primary tumour is detectable. […] There are various hypotheses on aetiology and pathogenesis. One tentative explanation for CUP is the stem cell theory of cancer. Asynchronous division of the premalignantly or malignantly transformed stem cells may produce daughter cells that do not grow locally but are able to metastasise. Given the favourable microenvironment of these metastases, these may spread to another site, even though no tumour develops in the tissue of origin. This hypothesis is supported by tumour genomics, with clonal evolution documented in various cancers (e.g., lung cancer).

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

  https://www.jcancer.org/v11p3919.htm

  Another relevant dispute is whether the prognosis of CUP patients is linked to the prognosis of the primary tumour or a genetic profile typical to CUP. The metastasis-prone behaviour of CUP may be related to a functional deficiency of certain metastasis-suppressor or tumour-suppressor genes. Identifying them will help to dispel the belief that dysregulation of one or more genes and their encoded proteins pushes systemic dissemination and primary regression. […] Klein et al. have suggested that neoplasm might develop from stem cells, without triggering a premalignant lesion or a primary tumour. These basic hypotheses have not been confirmed because studies conducted to date have yielded neither consistent nor specific gene/protein abnormalities 'pivotal’ to the development and survival of CUP.

• #15

  https://link.springer.com/article/10.1007/s12254-023-00935-9

  The pathogenesis of CUPs remains elusive. Rassy et al. suggested several possible causes for CUP carcinogenesis: […] CUP does not undergo type 1 progression, which involves the transformation from a premalignant condition to a malignant lesion. Instead, CUP follows type 2 progression, where a malignant lesion is present at disease onset without the prior development of a nascent primary tumor. […] CUP does not adhere to a linear progression model, characterized by a stepwise accumulation of genetic and epigenetic alterations throughout cancer development. Instead, it adheres to a parallel progression model, where metastases can arise early in the malignancy’s development. […] CUP may originate from the migration of deregulated premalignant or cancerous stem cells away from their natural tissues, leading to the formation of tumors in different locations.

• #16 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  In the context of CUP, metastasis might occur before local tumour growth as a consequence of two scenarios. […] Tumour cells are widely hypothesised to emigrate from their primary site by epithelial-to-mesenchymal transition (EMT). […] The EMT phenotype is associated with high histological grade, presence of visceral metastases and poor survival. […] The process that gives rise to CUP, characterised by early metastatic spread, regression of the primary site and aggressive course of the disease, is driven by multiple interdependent alterations in cell behaviour, including chromosomal alterations, self-sufficiency in growth signals, resistance to growth-inhibitory signals, reprogramming of energy metabolism, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis and evasion of immune destruction.

• #17 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  Clonal proliferation arises directly from normal stem cells or non-stem cells acquiring DNA alterations that result in the activation of stem-cell programmes according to a type 2 progression, which assumes the acquisition of a malignant phenotype directly without developing premalignant lesions. […] In the context of CUP, metastasis might occur before local tumour growth as a consequence of two scenarios. […] Tumour cells are widely hypothesised to emigrate from their primary site by epithelial-to-mesenchymal transition (EMT). […] The EMT phenotype is associated with high histological grade, presence of visceral metastases and poor survival. […] The process that gives rise to CUP, characterised by early metastatic spread, regression of the primary site and aggressive course of the disease, is driven by multiple interdependent alterations in cell behaviour, including chromosomal alterations, self-sufficiency in growth signals, resistance to growth-inhibitory signals, reprogramming of energy metabolism, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis and evasion of immune destruction.

• #18 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  Chromosomal instability (CIN) is a process that accelerates the rate of gains or losses of whole or large portions of chromosomes. […] Around 70% of patients with CUP show an enrichment in transcripts for proteins that function in DNA damage and homologous recombination repair networks, such as BRCA1, ATM and CHEK2, suggesting that CUP is chromosomally unstable. […] The most widely accepted molecular basis for CIN involves the oncogene-induced collapse of DNA replication forks, leading to double-stranded DNA breaks and genomic instability. […] The progression of tumorigenesis usually involves the activation of an angiogenic switch, which is required for the growth of a lesion beyond a certain size. […] It is hypothesised that CUP presents an angiogenic incompetence at the primary site, which thereby limits the development of the primary tumour.

• #19 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  The predominant alterations in the carcinogenic pathways have direct implications on the final morphology and natural history of CUP. […] Around 70% of patients with CUP show an enrichment in transcripts for proteins that function in DNA damage and homologous recombination repair networks, such as BRCA1, ATM and CHEK2, suggesting that CUP is chromosomally unstable. […] The most widely accepted molecular basis for CIN involves the oncogene-induced collapse of DNA replication forks, leading to double-stranded DNA breaks and genomic instability. […] The expression of p53 is reported in 4870% (overexpression in 53%) of patients with CUP, although it has no prognostic value for treatment benefit or survival. […] The ability of tumours to grow is determined not only by the rate of cell proliferation but also by the rate of cell attrition.

• #20 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  In the context of CUP, metastasis might occur before local tumour growth as a consequence of two scenarios. […] Tumour cells are widely hypothesised to emigrate from their primary site by epithelial-to-mesenchymal transition (EMT). […] The EMT phenotype is associated with high histological grade, presence of visceral metastases and poor survival. […] The process that gives rise to CUP, characterised by early metastatic spread, regression of the primary site and aggressive course of the disease, is driven by multiple interdependent alterations in cell behaviour, including chromosomal alterations, self-sufficiency in growth signals, resistance to growth-inhibitory signals, reprogramming of energy metabolism, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis and evasion of immune destruction.

• #21 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  Clonal proliferation arises directly from normal stem cells or non-stem cells acquiring DNA alterations that result in the activation of stem-cell programmes according to a type 2 progression, which assumes the acquisition of a malignant phenotype directly without developing premalignant lesions. […] In the context of CUP, metastasis might occur before local tumour growth as a consequence of two scenarios. […] Tumour cells are widely hypothesised to emigrate from their primary site by epithelial-to-mesenchymal transition (EMT). […] The EMT phenotype is associated with high histological grade, presence of visceral metastases and poor survival. […] The process that gives rise to CUP, characterised by early metastatic spread, regression of the primary site and aggressive course of the disease, is driven by multiple interdependent alterations in cell behaviour, including chromosomal alterations, self-sufficiency in growth signals, resistance to growth-inhibitory signals, reprogramming of energy metabolism, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis and evasion of immune destruction.

• #22 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  Chromosomal instability (CIN) is a process that accelerates the rate of gains or losses of whole or large portions of chromosomes. […] Around 70% of patients with CUP show an enrichment in transcripts for proteins that function in DNA damage and homologous recombination repair networks, such as BRCA1, ATM and CHEK2, suggesting that CUP is chromosomally unstable. […] The most widely accepted molecular basis for CIN involves the oncogene-induced collapse of DNA replication forks, leading to double-stranded DNA breaks and genomic instability. […] The progression of tumorigenesis usually involves the activation of an angiogenic switch, which is required for the growth of a lesion beyond a certain size. […] It is hypothesised that CUP presents an angiogenic incompetence at the primary site, which thereby limits the development of the primary tumour.

• #23 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  The expression of the anti-apoptotic protein Bcl-2 is reported in 65% (overexpression in 40%) of patients with CUP. […] The progression of tumorigenesis usually involves the activation of an angiogenic switch, which is required for the growth of a lesion beyond a certain size. […] It is hypothesised that CUP presents an angiogenic incompetence at the primary site, which thereby limits the development of the primary tumour. […] Metalloproteinase (MMP)-2 and MMP-9 are expressed in 69% (overexpression in 49%) and 49% (overexpression in 36%) of patients with CUP, respectively. […] As part of the process of tumorigenesis, cancer cells inhibit the immune system partly by targeting the inhibitory pathway of programmed cell death protein (PD-1) and its ligand (PD-L1). […] We have sought here to extend the concept of cancer hallmarks to CUP in order to provide a useful conceptual framework for understanding the enigmatic biology of CUP. […] Current research focuses mainly on growth factor independence, and little research has been performed on the remaining hallmarks, despite their important role in promoting and regulating the carcinogenesis of CUP.

• #24 Carcinoma of Unknown Primary Origin

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2631214/

  Carcinoma of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. […] Whether CUP is a distinct molecular genotype-phenotype relative to metastases of known cancers is unknown. However, use of a robust immunohistochemical panel and emerging molecular data may permit development of a tailored treatment algorithm for CUP patients that will include appropriate use of targeted agents. […] The roles of chromosomal and molecular abnormalities in CUP have been evaluated in several studies, but to date no CUP characteristics have been identified that are unique relative to those of metastases from known primary tumors. […] It has been theorized that in CUP, the angiogenic incompetence of the primary tumor leads to marked apoptosis and cell turnover, resulting in a cancer that acquires a metastatic phenotype; however, this theory cannot be clinically tested. […] Whether CUP has a molecular genotype-phenotype that is distinct from metastases of known primary tumors remains to be elucidated. The identification of specific CUP-related molecular and biochemical targets may help us identify appropriate targeted agents for individual patients with this disease.

• #25 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  The expression of the anti-apoptotic protein Bcl-2 is reported in 65% (overexpression in 40%) of patients with CUP. […] The expression of p53 is reported in 4870% (overexpression in 53%) of patients with CUP, although it has no prognostic value for treatment benefit or survival. […] The expression levels of p21 correlate with different CUP subgroups, with high p21 expression seen predominantly in nodal CUP. […] The ability of tumours to grow is determined not only by the rate of cell proliferation but also by the rate of cell attrition. […] The expression of phosphorylated AKT (pAKT) is reported in 73.2% of patients with CUP, and is associated with worse survival. […] The expression of RAS is reported in 92% (overexpression 23%) of patients with CUP. […] The expression of cMET is prevalent in the squamous cervical and inguinal nodal subgroups (100% positive for cMET) and is associated with fewer metastatic sites and low-grade squamous tumours. […] The poor clinical outcome is explained by the potentiating effects on angiogenesis (by activating HIF1a), proliferation (by stimulating MAPK pathway and inhibiting p53) and invasion (partly via MMP-9).

• #26 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  The predominant alterations in the carcinogenic pathways have direct implications on the final morphology and natural history of CUP. […] Around 70% of patients with CUP show an enrichment in transcripts for proteins that function in DNA damage and homologous recombination repair networks, such as BRCA1, ATM and CHEK2, suggesting that CUP is chromosomally unstable. […] The most widely accepted molecular basis for CIN involves the oncogene-induced collapse of DNA replication forks, leading to double-stranded DNA breaks and genomic instability. […] The expression of p53 is reported in 4870% (overexpression in 53%) of patients with CUP, although it has no prognostic value for treatment benefit or survival. […] The ability of tumours to grow is determined not only by the rate of cell proliferation but also by the rate of cell attrition.

• #27 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  The expression of the anti-apoptotic protein Bcl-2 is reported in 65% (overexpression in 40%) of patients with CUP. […] The expression of p53 is reported in 4870% (overexpression in 53%) of patients with CUP, although it has no prognostic value for treatment benefit or survival. […] The expression levels of p21 correlate with different CUP subgroups, with high p21 expression seen predominantly in nodal CUP. […] The ability of tumours to grow is determined not only by the rate of cell proliferation but also by the rate of cell attrition. […] The expression of phosphorylated AKT (pAKT) is reported in 73.2% of patients with CUP, and is associated with worse survival. […] The expression of RAS is reported in 92% (overexpression 23%) of patients with CUP. […] The expression of cMET is prevalent in the squamous cervical and inguinal nodal subgroups (100% positive for cMET) and is associated with fewer metastatic sites and low-grade squamous tumours. […] The poor clinical outcome is explained by the potentiating effects on angiogenesis (by activating HIF1a), proliferation (by stimulating MAPK pathway and inhibiting p53) and invasion (partly via MMP-9).

• #28 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  The expression of the anti-apoptotic protein Bcl-2 is reported in 65% (overexpression in 40%) of patients with CUP. […] The progression of tumorigenesis usually involves the activation of an angiogenic switch, which is required for the growth of a lesion beyond a certain size. […] It is hypothesised that CUP presents an angiogenic incompetence at the primary site, which thereby limits the development of the primary tumour. […] Metalloproteinase (MMP)-2 and MMP-9 are expressed in 69% (overexpression in 49%) and 49% (overexpression in 36%) of patients with CUP, respectively. […] As part of the process of tumorigenesis, cancer cells inhibit the immune system partly by targeting the inhibitory pathway of programmed cell death protein (PD-1) and its ligand (PD-L1). […] We have sought here to extend the concept of cancer hallmarks to CUP in order to provide a useful conceptual framework for understanding the enigmatic biology of CUP. […] Current research focuses mainly on growth factor independence, and little research has been performed on the remaining hallmarks, despite their important role in promoting and regulating the carcinogenesis of CUP.

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

  https://www.jcancer.org/v11p3919.htm

  The aggressive behaviour of CUP may be due to initial immunosuppression, which may lead to mutation accumulation. The unchecked spread of tumour occurs upon escape from the suppressed state. […] Although the primary tumour in CUP is thought to be dormant, CUP patients have early distant metastases. The metastatic tendency may explain poor prognosis, and metastasis is considered to be the cause of death in most patients with primary cancers. Metastasis involves several genes, and it has been shown that some essential metastatic genes are overexpressed in CUP: vessel endothelial growth factor, and matrix metalloproteinases, proteolytic enzymes that mediate local invasion and metastasis. […] The different specificities of antibodies may explain the discordance between IHC data and data obtained from the mutational analysis of genes for wild-type and mutated genes. For example, the varying impact of P53-regulating factors such as murine double minute-2, p14 alternate reading frame and p21 due to presence of mutations outside Exons 5-9 of p53.

• #30 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  Cancer of unknown primary (CUP) affects a small percentage of the general population. […] The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. […] Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. […] Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. […] CUP can be viewed as an enigmatic cancer, as the accuracy of the diagnosis and the efficacy of the treatment are questioned. […] CUP has been hypothesised to possess a genetic signature that is specific for its primary site and a second genetic signature that is primary-independent, pro-metastatic and possibly CUP-specific, which differentiates the known and unknown primary tumours.

• #31 Frontiers | Does Cancer of Unknown Primary (CUP) Truly Exist as a Distinct Cancer Entity?

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00402/full

  Cancer of unknown primary (CUP) designates an enigmatic cancer entity with histologic confirmation of malignancy from a metastasis but no identifiable primary tumor in spite of a thorough diagnostic work-up. […] Metastatic spread appears to take place in the early stages of tumor evolution, with CUP metastases subsequently undergoing genetic evolution toward a chromosomally highly complex and instable karyotype independent from the primary tumor. […] New insights into the mechanisms of metastatic seed in cancers also provide explanatory models for the enigmatic phenomenon of an undetectable primary tumor. […] This model of early branching of the primary tumor and metastases evolution and their long independent trajectory under selection pressure in different niches obviously accounts for genetic and growth discrepancies between primary and metastases.

• #32 Frontiers | Does Cancer of Unknown Primary (CUP) Truly Exist as a Distinct Cancer Entity?

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00402/full

  Cytogenetic data support this model as well. […] In view of chromosomal instability (CIN) as a driver of tumor evolution this karyotypic complexity in CUP reflects the aggressiveness of metastatic growth in this entity. […] Interestingly, evidence suggests that primary tumors in general actively modify future metastatic sites by tumor-secreted factors to make them susceptible to metastatic seed, a phenomenon called „premetastatic niche formation.”

• #33 Frontiers | Does Cancer of Unknown Primary (CUP) Truly Exist as a Distinct Cancer Entity?

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00402/full

  Cytogenetic data support this model as well. […] In view of chromosomal instability (CIN) as a driver of tumor evolution this karyotypic complexity in CUP reflects the aggressiveness of metastatic growth in this entity. […] Interestingly, evidence suggests that primary tumors in general actively modify future metastatic sites by tumor-secreted factors to make them susceptible to metastatic seed, a phenomenon called „premetastatic niche formation.”

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

  https://www.jcancer.org/v11p3919.htm

  The aggressive behaviour of CUP may be due to initial immunosuppression, which may lead to mutation accumulation. The unchecked spread of tumour occurs upon escape from the suppressed state. […] Although the primary tumour in CUP is thought to be dormant, CUP patients have early distant metastases. The metastatic tendency may explain poor prognosis, and metastasis is considered to be the cause of death in most patients with primary cancers. Metastasis involves several genes, and it has been shown that some essential metastatic genes are overexpressed in CUP: vessel endothelial growth factor, and matrix metalloproteinases, proteolytic enzymes that mediate local invasion and metastasis. […] The different specificities of antibodies may explain the discordance between IHC data and data obtained from the mutational analysis of genes for wild-type and mutated genes. For example, the varying impact of P53-regulating factors such as murine double minute-2, p14 alternate reading frame and p21 due to presence of mutations outside Exons 5-9 of p53.

• #35 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  The expression of the anti-apoptotic protein Bcl-2 is reported in 65% (overexpression in 40%) of patients with CUP. […] The progression of tumorigenesis usually involves the activation of an angiogenic switch, which is required for the growth of a lesion beyond a certain size. […] It is hypothesised that CUP presents an angiogenic incompetence at the primary site, which thereby limits the development of the primary tumour. […] Metalloproteinase (MMP)-2 and MMP-9 are expressed in 69% (overexpression in 49%) and 49% (overexpression in 36%) of patients with CUP, respectively. […] As part of the process of tumorigenesis, cancer cells inhibit the immune system partly by targeting the inhibitory pathway of programmed cell death protein (PD-1) and its ligand (PD-L1). […] We have sought here to extend the concept of cancer hallmarks to CUP in order to provide a useful conceptual framework for understanding the enigmatic biology of CUP. […] Current research focuses mainly on growth factor independence, and little research has been performed on the remaining hallmarks, despite their important role in promoting and regulating the carcinogenesis of CUP.

• #36

  https://link.springer.com/article/10.1007/s12254-023-00935-9

  The pathogenesis of CUPs remains elusive. Rassy et al. suggested several possible causes for CUP carcinogenesis: […] CUP does not undergo type 1 progression, which involves the transformation from a premalignant condition to a malignant lesion. Instead, CUP follows type 2 progression, where a malignant lesion is present at disease onset without the prior development of a nascent primary tumor. […] CUP does not adhere to a linear progression model, characterized by a stepwise accumulation of genetic and epigenetic alterations throughout cancer development. Instead, it adheres to a parallel progression model, where metastases can arise early in the malignancy’s development. […] CUP may originate from the migration of deregulated premalignant or cancerous stem cells away from their natural tissues, leading to the formation of tumors in different locations.

• #37 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  The evidence for germline susceptibility to CUP is weak, and cannot be confirmed by familial studies as the occurrence of cancers in relatives might be incidental and not related to genetic susceptibility. […] However, familial studies are informative of both genetic and environmental factors and might be informative of the CUP pathogenesis. […] According to current understanding, the process of tumorigenesis involves the consecutive sequence of clonal proliferation, invasion and intravasation of cancer cells from the primary tumour, dissemination through the circulation, extravasation in different organs and colonisation at metastatic sites. […] Clonal proliferation arises directly from normal stem cells or non-stem cells acquiring DNA alterations that result in the activation of stem-cell programmes according to a type 2 progression, which assumes the acquisition of a malignant phenotype directly without developing premalignant lesions.

• #38

  https://link.springer.com/article/10.1007/s12254-023-00935-9

  The pathogenesis of CUPs remains elusive. Rassy et al. suggested several possible causes for CUP carcinogenesis: […] CUP does not undergo type 1 progression, which involves the transformation from a premalignant condition to a malignant lesion. Instead, CUP follows type 2 progression, where a malignant lesion is present at disease onset without the prior development of a nascent primary tumor. […] CUP does not adhere to a linear progression model, characterized by a stepwise accumulation of genetic and epigenetic alterations throughout cancer development. Instead, it adheres to a parallel progression model, where metastases can arise early in the malignancy’s development. […] CUP may originate from the migration of deregulated premalignant or cancerous stem cells away from their natural tissues, leading to the formation of tumors in different locations.

• #39 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7156745/

  The evidence for germline susceptibility to CUP is weak, and cannot be confirmed by familial studies as the occurrence of cancers in relatives might be incidental and not related to genetic susceptibility. […] However, familial studies are informative of both genetic and environmental factors and might be informative of the CUP pathogenesis. […] According to current understanding, the process of tumorigenesis involves the consecutive sequence of clonal proliferation, invasion and intravasation of cancer cells from the primary tumour, dissemination through the circulation, extravasation in different organs and colonisation at metastatic sites. […] Clonal proliferation arises directly from normal stem cells or non-stem cells acquiring DNA alterations that result in the activation of stem-cell programmes according to a type 2 progression, which assumes the acquisition of a malignant phenotype directly without developing premalignant lesions.

• #40 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  Clonal proliferation arises directly from normal stem cells or non-stem cells acquiring DNA alterations that result in the activation of stem-cell programmes according to a type 2 progression, which assumes the acquisition of a malignant phenotype directly without developing premalignant lesions. […] In the context of CUP, metastasis might occur before local tumour growth as a consequence of two scenarios. […] Tumour cells are widely hypothesised to emigrate from their primary site by epithelial-to-mesenchymal transition (EMT). […] The EMT phenotype is associated with high histological grade, presence of visceral metastases and poor survival. […] The process that gives rise to CUP, characterised by early metastatic spread, regression of the primary site and aggressive course of the disease, is driven by multiple interdependent alterations in cell behaviour, including chromosomal alterations, self-sufficiency in growth signals, resistance to growth-inhibitory signals, reprogramming of energy metabolism, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis and evasion of immune destruction.

• #41

  https://link.springer.com/article/10.1007/s12254-023-00935-9

  The pathogenesis of CUPs remains elusive. Rassy et al. suggested several possible causes for CUP carcinogenesis: […] CUP does not undergo type 1 progression, which involves the transformation from a premalignant condition to a malignant lesion. Instead, CUP follows type 2 progression, where a malignant lesion is present at disease onset without the prior development of a nascent primary tumor. […] CUP does not adhere to a linear progression model, characterized by a stepwise accumulation of genetic and epigenetic alterations throughout cancer development. Instead, it adheres to a parallel progression model, where metastases can arise early in the malignancy’s development. […] CUP may originate from the migration of deregulated premalignant or cancerous stem cells away from their natural tissues, leading to the formation of tumors in different locations.

• #42 Frontiers | Does Cancer of Unknown Primary (CUP) Truly Exist as a Distinct Cancer Entity?

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00402/full

  Cancer of unknown primary (CUP) designates an enigmatic cancer entity with histologic confirmation of malignancy from a metastasis but no identifiable primary tumor in spite of a thorough diagnostic work-up. […] Metastatic spread appears to take place in the early stages of tumor evolution, with CUP metastases subsequently undergoing genetic evolution toward a chromosomally highly complex and instable karyotype independent from the primary tumor. […] New insights into the mechanisms of metastatic seed in cancers also provide explanatory models for the enigmatic phenomenon of an undetectable primary tumor. […] This model of early branching of the primary tumor and metastases evolution and their long independent trajectory under selection pressure in different niches obviously accounts for genetic and growth discrepancies between primary and metastases.

• #43

  https://link.springer.com/article/10.1007/s12254-023-00935-9

  Metastatic spread occurs, when motile cells migrate prior to uncontrolled local proliferation of non-motile neoplastic cells at the primary site. Alternatively, migratory cells can disseminate from a primary tumor that initially formed but has subsequently been selectively eliminated by microenvironmental factors, thereby favoring the outgrowth of tumor cells at the metastatic site.

• #44 Cancer of unknown primary origin – Wikipedia

  https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin

  Cancer of unknown primary source is not a single type of cancer, although researchers have attempted to find a common characteristic that explains why a cancer might spread very early without causing symptoms at the site of origin. […] It is generally accepted that cancer of unknown primary site exists because the primary tumor is not identified due to clinical or technological inefficiencies, or because the primary tumor regresses or stays dormant after spreading the cancer cells that generate the metastases. […] Because stem cells have a natural ability to migrate and also play a key role in cancer development, it has been proposed that a cancer of unknown primary site may form when deregulated, premalignant or cancerous stem cells migrate away from their natural tissue and give rise to a cancer in the new site before or without generating a tumor in their original tissue. […] Forming a tumor in a tissue is not a prerequisite for stem cells to move away from that tissue. […] However, stem cells can also migrate away from their natural tissue without generating a cancer there. […] This view of CUP may provide relief to health professionals and patients.

• #45

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The aim is to not only improve survival rates when compared with current empiric treatment but also to reduce unnecessary side effects from ineffective drugs and provide a more complete diagnosis. […] The mutational profile of cancer reflects the aberrant functioning and processes of the neoplastic cells. […] The presence of these signatures can be used as useful indicators of the primary site of the tumour. […] While the primary site is unknown, CUP can be classified into two subgroups to aid in therapeutic decision making. […] Importantly, patients in whom primary anatomic site is strongly suggested by clinical/pathologic criteria should no longer be considered CUP, and treatment should proceed in accordance with established clinical guidelines for that tumour type. […] An integrated diagnostic report is ideal, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. […] Research and improved understanding of genomic variations driving tumour development is critically important for the development of new drug therapies.

• #46

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The aim is to not only improve survival rates when compared with current empiric treatment but also to reduce unnecessary side effects from ineffective drugs and provide a more complete diagnosis. […] The mutational profile of cancer reflects the aberrant functioning and processes of the neoplastic cells. […] The presence of these signatures can be used as useful indicators of the primary site of the tumour. […] While the primary site is unknown, CUP can be classified into two subgroups to aid in therapeutic decision making. […] Importantly, patients in whom primary anatomic site is strongly suggested by clinical/pathologic criteria should no longer be considered CUP, and treatment should proceed in accordance with established clinical guidelines for that tumour type. […] An integrated diagnostic report is ideal, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. […] Research and improved understanding of genomic variations driving tumour development is critically important for the development of new drug therapies.

• #47 Carcinoma of Unknown Primary Origin

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2631214/

  Carcinoma of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. […] Whether CUP is a distinct molecular genotype-phenotype relative to metastases of known cancers is unknown. However, use of a robust immunohistochemical panel and emerging molecular data may permit development of a tailored treatment algorithm for CUP patients that will include appropriate use of targeted agents. […] The roles of chromosomal and molecular abnormalities in CUP have been evaluated in several studies, but to date no CUP characteristics have been identified that are unique relative to those of metastases from known primary tumors. […] It has been theorized that in CUP, the angiogenic incompetence of the primary tumor leads to marked apoptosis and cell turnover, resulting in a cancer that acquires a metastatic phenotype; however, this theory cannot be clinically tested. […] Whether CUP has a molecular genotype-phenotype that is distinct from metastases of known primary tumors remains to be elucidated. The identification of specific CUP-related molecular and biochemical targets may help us identify appropriate targeted agents for individual patients with this disease.

• #48 Molecular Profiling for Cancers of Unknown Primary Origin

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/molecular-profiling-for-cancers-of-unknown-primary-origin/

  Although the true tissue of origin may not be identifiable in any given case, recent evidence suggests it may be useful to provide site-specific treatment based on tumor type (J. Hainsworth F. Greco, 2023). […] The authors concluded that mutations of relevant driver genes were present in vast majority of CUP tumors and that these genes may carry impact on prognosis and targeted therapy (Loffler et al., 2016). […] The authors concluded that their results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers (Groschel et al., 2016). […] The authors concluded that the clinical benefit of using molecular profiling to guide treatment decisions in CUP remains to be determined. The NCCN also states that currently, there is no evidence of improved outcomes with the use of site-specific therapy guided by molecular testing results in patients with CUP (NCCN, 2024).

• #49 Molecular Profiling for Cancers of Unknown Primary Origin

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/molecular-profiling-for-cancers-of-unknown-primary-origin/

  Cancers of unknown primary origin (CUPs) are defined as the four to five percent of invasive cancers for which no primary site can be identified despite an extensive diagnostic work-up (Fizazi et al., 2015; Varadhachary Raber, 2014). […] Given their rapid progression and dissemination, it was assumed that regardless of the site of origin, the tumors in unknown primary cancers shared biologic properties common to their pathogenesis and that identification of the exact tissue of origin would not have a substantial effect on therapeutic approaches or survival. However, biologic events that allow development of metastases without a discernable tumor at the primary site have not yet been determined (Varadhachary Raber, 2014). […] Tumors in unknown primary cancer despite different degrees of loss of differentiation retain the signature of their primary origin, even after metastasis (Fizazi et al., 2015).

• #50

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. […] CUP represents a morphological, immunohistochemical and molecular diagnostic challenge in surgical pathology. […] Increasingly, this involves the use of predictive biomarkers using additional immunohistochemistry and molecular assays beyond those traditionally used to detect the primary site. […] The majority of these tumours are broadly subtyped as metastatic adenocarcinoma (60%), squamous cell (5%), and neuroendocrine carcinoma (2%) or are poorly or undifferentiated (30%).

• #51

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The high grade undifferentiated carcinoma is a more challenging entity, both in terms of determining the primary site and in offering therapeutics options. […] Glandular morphology suggests a metastatic adenocarcinoma on HE, with columnar cells with intracytoplasmic and/or extracellular mucin. […] Neuroendocrine tumours are grouped as well or poorly differentiated regardless of primary site, while grading varies according to tissue of origin (ToO). […] A variety of other morphologic patterns can also be encountered such as epithelioid, small round blue, plasmacytoid, spindled, or undifferentiated morphology. […] The traditional cancer classification paradigm of tissue and organ type is changing as more cancers are now subclassified by their molecular characteristics with the aim of providing personalised treatment strategies.

• #52 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://www.mdpi.com/resolver?pii=cancers13030451

  However, the advent of precision medicine and the availability of multi-omics databases is rapidly transforming the clinical management of different cancer types, shifting to a more personalized treatment approach, regardless of the primary site. […] Here, we review the current knowledge on CUP research, focusing on patients’ current management, treatment options, and the latest approaches on CUP diagnostics based on molecular profiling and epigenetic characterization of the tumor.

• #53

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The aim is to not only improve survival rates when compared with current empiric treatment but also to reduce unnecessary side effects from ineffective drugs and provide a more complete diagnosis. […] The mutational profile of cancer reflects the aberrant functioning and processes of the neoplastic cells. […] The presence of these signatures can be used as useful indicators of the primary site of the tumour. […] While the primary site is unknown, CUP can be classified into two subgroups to aid in therapeutic decision making. […] Importantly, patients in whom primary anatomic site is strongly suggested by clinical/pathologic criteria should no longer be considered CUP, and treatment should proceed in accordance with established clinical guidelines for that tumour type. […] An integrated diagnostic report is ideal, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. […] Research and improved understanding of genomic variations driving tumour development is critically important for the development of new drug therapies.

• #54 The Impact of Molecular Testing on Treatment of Cancer of Unknown Primary Origin

  https://www.cancernetwork.com/view/impact-molecular-testing-treatment-cancer-unknown-primary-origin

  The clinical biology of CUP remains a puzzle. The mechanism by which a very small clinically undetectable primary site can metastasize and produce larger clinically demonstrable metastases is unknown. Perhaps detailed genomic analysis of these cancers may eventually explain this syndrome. […] The CUP syndrome occurs in patients without an anatomically defined primary site. […] A molecular profiling assay performed on the biopsy specimen, particularly in patients with an inconclusive IHC diagnosis, can provide a single-tissue-of-origin diagnosis in most of these patients and complements standard pathology. […] In CUP patients the primary site is not clinically detectable, and a tissue of origin must be determined by the nature of the metastatic cells in the biopsy specimen, as assessed via the appropriate use of classic histology, IHC stains, and a molecular profiling assay. […] Site-specific and molecularly targeted therapies continue to improve for several types of advanced solid tumors. It is also logical to apply these treatments to CUP patients diagnosed with specific cancer types.

• #55

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. […] CUP represents a morphological, immunohistochemical and molecular diagnostic challenge in surgical pathology. […] Increasingly, this involves the use of predictive biomarkers using additional immunohistochemistry and molecular assays beyond those traditionally used to detect the primary site. […] The majority of these tumours are broadly subtyped as metastatic adenocarcinoma (60%), squamous cell (5%), and neuroendocrine carcinoma (2%) or are poorly or undifferentiated (30%).

• #56

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. […] CUP represents a morphological, immunohistochemical and molecular diagnostic challenge in surgical pathology. […] Increasingly, this involves the use of predictive biomarkers using additional immunohistochemistry and molecular assays beyond those traditionally used to detect the primary site. […] The majority of these tumours are broadly subtyped as metastatic adenocarcinoma (60%), squamous cell (5%), and neuroendocrine carcinoma (2%) or are poorly or undifferentiated (30%).

• #57 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://www.mdpi.com/resolver?pii=cancers13030451

  Patients with cancer of unknown primary site suffer the burden of an uncertain disease, which is characterized by the impossibility to identify the tissue where the tumor has originated. […] The identification of the primary site of a tumor is of great importance for the patient to have access to site-specific treatments and be enrolled in clinical trials. […] Therefore, patients with cancer of unknown primary have reduced therapeutic opportunities and poor prognosis. […] Advancements have been made in the molecular characterization of this tumor, which could be used to infer the tumor site-of-origin and thus broaden the diagnostic outcome. […] Moreover, we describe here the novel therapeutic opportunities that are based on the genetic and immunophenotypic characterization of the tumor, and thus independent from the tumor type, which could provide most benefit to patients with cancer of unknown primary.

• #58

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The high grade undifferentiated carcinoma is a more challenging entity, both in terms of determining the primary site and in offering therapeutics options. […] Glandular morphology suggests a metastatic adenocarcinoma on HE, with columnar cells with intracytoplasmic and/or extracellular mucin. […] Neuroendocrine tumours are grouped as well or poorly differentiated regardless of primary site, while grading varies according to tissue of origin (ToO). […] A variety of other morphologic patterns can also be encountered such as epithelioid, small round blue, plasmacytoid, spindled, or undifferentiated morphology. […] The traditional cancer classification paradigm of tissue and organ type is changing as more cancers are now subclassified by their molecular characteristics with the aim of providing personalised treatment strategies.

• #59 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://www.mdpi.com/resolver?pii=cancers13030451

  Patients with cancer of unknown primary site suffer the burden of an uncertain disease, which is characterized by the impossibility to identify the tissue where the tumor has originated. […] The identification of the primary site of a tumor is of great importance for the patient to have access to site-specific treatments and be enrolled in clinical trials. […] Therefore, patients with cancer of unknown primary have reduced therapeutic opportunities and poor prognosis. […] Advancements have been made in the molecular characterization of this tumor, which could be used to infer the tumor site-of-origin and thus broaden the diagnostic outcome. […] Moreover, we describe here the novel therapeutic opportunities that are based on the genetic and immunophenotypic characterization of the tumor, and thus independent from the tumor type, which could provide most benefit to patients with cancer of unknown primary.

• #60 Cancer of Unknown Primary: Diagnosis and Treatment

  https://www.ekjm.org/journal/view.php?number=25767

  Cancer of unknown primary (CUP) is a heterogenous group of cancers for which the anatomical site of origin is unidentifiable on the basis of standard evaluation and imaging. CUPs account for 2-5% of all malignancies and are characterized by early metastatic dissemination, aggressive clinical course, and poor response to palliative chemotherapy. […] Evidence supporting the clinical use of molecular tissue of origin (TOO) tests is still lacking. Two recent randomized clinical trials failed to show the benefit of TOO-based site-specific therapy over empirical chemotherapy. In an era of precision medicine, the use of comprehensive molecular profiling will provide opportunities to identify patient subsets who are susceptible to targeted therapies and immunotherapies. […] The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis. […] Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies.

• #61 Cancer of unknown primary site in the mandibular region: A case report

  https://www.spandidos-publications.com/10.3892/ol.2023.13796

  Gene expression profiles can aid in the identification of primary tumor sites and targeted mutations. Liquid biopsy is a novel technique to aid CUP diagnosis via gene expression profiling and overcomes some limitations of tumor biopsy. […] The prognosis of CUP is worse than that for most other tumors. There is currently no standard chemotherapy regimen for treatment, but empiric platinum or paclitaxel-based chemotherapy is often used, even though the level of evidence supporting this method recommendation is low. […] Whether immune checkpoint inhibitors (ICIs) are an effective CUP treatment option is also currently an open question. ICIs are actively being evaluated in CUP given their theoretical ability to mount an effective antitumor immune response. […] In conclusion, the diagnosis and treatment of CUP presents difficulties and results in a poor prognosis.

• #62 Metastatic Cancer With Unknown Primary Site: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/280505-overview

  CUP is characterized by an aggressive course and resistance to conventional chemotherapy. Nevertheless, a precise pathologic diagnosis with next-generation sequencing may identify targetable mutations and help guide therapy. For example, in patients whose tumors are found to have high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), treatment with an immune checkpoint inhibitor (programmed cell death inhibitor) may significantly improve survival.

• #63 Cancer of unknown primary site in the mandibular region: A case report

  https://www.spandidos-publications.com/10.3892/ol.2023.13796

  Gene expression profiles can aid in the identification of primary tumor sites and targeted mutations. Liquid biopsy is a novel technique to aid CUP diagnosis via gene expression profiling and overcomes some limitations of tumor biopsy. […] The prognosis of CUP is worse than that for most other tumors. There is currently no standard chemotherapy regimen for treatment, but empiric platinum or paclitaxel-based chemotherapy is often used, even though the level of evidence supporting this method recommendation is low. […] Whether immune checkpoint inhibitors (ICIs) are an effective CUP treatment option is also currently an open question. ICIs are actively being evaluated in CUP given their theoretical ability to mount an effective antitumor immune response. […] In conclusion, the diagnosis and treatment of CUP presents difficulties and results in a poor prognosis.

• #64 Molecular Profiling for Cancers of Unknown Primary Origin

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/molecular-profiling-for-cancers-of-unknown-primary-origin/

  Although the true tissue of origin may not be identifiable in any given case, recent evidence suggests it may be useful to provide site-specific treatment based on tumor type (J. Hainsworth F. Greco, 2023). […] The authors concluded that mutations of relevant driver genes were present in vast majority of CUP tumors and that these genes may carry impact on prognosis and targeted therapy (Loffler et al., 2016). […] The authors concluded that their results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers (Groschel et al., 2016). […] The authors concluded that the clinical benefit of using molecular profiling to guide treatment decisions in CUP remains to be determined. The NCCN also states that currently, there is no evidence of improved outcomes with the use of site-specific therapy guided by molecular testing results in patients with CUP (NCCN, 2024).

• #65 Carcinoma of Unknown Primary Origin

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2631214/

  Carcinoma of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. […] Whether CUP is a distinct molecular genotype-phenotype relative to metastases of known cancers is unknown. However, use of a robust immunohistochemical panel and emerging molecular data may permit development of a tailored treatment algorithm for CUP patients that will include appropriate use of targeted agents. […] The roles of chromosomal and molecular abnormalities in CUP have been evaluated in several studies, but to date no CUP characteristics have been identified that are unique relative to those of metastases from known primary tumors. […] It has been theorized that in CUP, the angiogenic incompetence of the primary tumor leads to marked apoptosis and cell turnover, resulting in a cancer that acquires a metastatic phenotype; however, this theory cannot be clinically tested. […] Whether CUP has a molecular genotype-phenotype that is distinct from metastases of known primary tumors remains to be elucidated. The identification of specific CUP-related molecular and biochemical targets may help us identify appropriate targeted agents for individual patients with this disease.

• #66 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? | British Journal of Cancer

  https://www.nature.com/articles/s41416-019-0723-z

  The expression of the anti-apoptotic protein Bcl-2 is reported in 65% (overexpression in 40%) of patients with CUP. […] The progression of tumorigenesis usually involves the activation of an angiogenic switch, which is required for the growth of a lesion beyond a certain size. […] It is hypothesised that CUP presents an angiogenic incompetence at the primary site, which thereby limits the development of the primary tumour. […] Metalloproteinase (MMP)-2 and MMP-9 are expressed in 69% (overexpression in 49%) and 49% (overexpression in 36%) of patients with CUP, respectively. […] As part of the process of tumorigenesis, cancer cells inhibit the immune system partly by targeting the inhibitory pathway of programmed cell death protein (PD-1) and its ligand (PD-L1). […] We have sought here to extend the concept of cancer hallmarks to CUP in order to provide a useful conceptual framework for understanding the enigmatic biology of CUP. […] Current research focuses mainly on growth factor independence, and little research has been performed on the remaining hallmarks, despite their important role in promoting and regulating the carcinogenesis of CUP.

• #67 Carcinoma of Unknown Primary Origin

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2631214/

  Carcinoma of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. […] Whether CUP is a distinct molecular genotype-phenotype relative to metastases of known cancers is unknown. However, use of a robust immunohistochemical panel and emerging molecular data may permit development of a tailored treatment algorithm for CUP patients that will include appropriate use of targeted agents. […] The roles of chromosomal and molecular abnormalities in CUP have been evaluated in several studies, but to date no CUP characteristics have been identified that are unique relative to those of metastases from known primary tumors. […] It has been theorized that in CUP, the angiogenic incompetence of the primary tumor leads to marked apoptosis and cell turnover, resulting in a cancer that acquires a metastatic phenotype; however, this theory cannot be clinically tested. […] Whether CUP has a molecular genotype-phenotype that is distinct from metastases of known primary tumors remains to be elucidated. The identification of specific CUP-related molecular and biochemical targets may help us identify appropriate targeted agents for individual patients with this disease.

• #68

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The aim is to not only improve survival rates when compared with current empiric treatment but also to reduce unnecessary side effects from ineffective drugs and provide a more complete diagnosis. […] The mutational profile of cancer reflects the aberrant functioning and processes of the neoplastic cells. […] The presence of these signatures can be used as useful indicators of the primary site of the tumour. […] While the primary site is unknown, CUP can be classified into two subgroups to aid in therapeutic decision making. […] Importantly, patients in whom primary anatomic site is strongly suggested by clinical/pathologic criteria should no longer be considered CUP, and treatment should proceed in accordance with established clinical guidelines for that tumour type. […] An integrated diagnostic report is ideal, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. […] Research and improved understanding of genomic variations driving tumour development is critically important for the development of new drug therapies.

• #69 AI-based pathology predicts origins for cancers of unknown primary | Nature

  https://www.nature.com/articles/s41586-021-03512-4

  Cancer of unknown primary (CUP) origin is an enigmatic group of diagnoses in which the primary anatomical site of tumour origin cannot be determined. This poses a considerable challenge, as modern therapeutics are predominantly specific to the primary tumour. Recent research has focused on using genomics and transcriptomics to identify the origin of a tumour. However, genomic testing is not always performed and lacks clinical penetration in low-resource settings. Here, to overcome these challenges, we present a deep-learning-based algorithm Tumour Origin Assessment via Deep Learning (TOAD) that can provide a differential diagnosis for the origin of the primary tumour using routinely acquired histology slides. We used whole-slide images of tumours with known primary origins to train a model that simultaneously identifies the tumour as primary or metastatic and predicts its site of origin. On our held-out test set of tumours with known primary origins, the model achieved a top-1 accuracy of 0.83 and a top-3 accuracy of 0.96, whereas on our external test set it achieved top-1 and top-3 accuracies of 0.80 and 0.93, respectively. We further curated a dataset of 317 cases of CUP for which a differential diagnosis was assigned. Our model predictions resulted in concordance for 61% of cases and a top-3 agreement of 82%. TOAD can be used as an assistive tool to assign a differential diagnosis to complicated cases of metastatic tumours and CUPs and could be used in conjunction with or in lieu of ancillary tests and extensive diagnostic work-ups to reduce the occurrence of CUP.

• #70 AI-based pathology predicts origins for cancers of unknown primary | Nature

  https://www.nature.com/articles/s41586-021-03512-4

  The model was first trained and tested on tumours of known primary origins. For model development and testing, we collected, in total, 32,537 HE digitized diagnostic slides (from 29,107 patients) with confirmed diagnosis and randomly sampled 70% of cases (22,833 slides) to train the model and 20% of cases (6,499 slides) were held-out for evaluation. The remaining 10% of cases (3,205 slides) was used for validation during training to select the best performing model. To further assess the ability of the model to generalize on data from sources and staining protocols that it did not encounter during training, we also evaluated the model on an external test cohort of 682 cases, submitted from more than 200 US and international medical centres. The model was then assessed on increasingly difficult cases of metastatic tumours. Lastly, to assess the ability of the model to inform meaningful predictions for origins of cancers that cannot be readily diagnosed by human experts using HE histology alone, we curated an additional diverse dataset of 743 cases of CUP sourced from institutions across the country and outside the USA. Although the primary cancer could not be initially assigned for all of these cases based on HE histology alone, using EMRs and evidence from clinical and ancillary tests, we identified a subset of 317 cases for which a primary differential was eventually assigned over the course of the patients history. We validated our model against the recorded primary differential for agreement, showcasing the applicability of the model to cases without clear morphological indication for a particular primary cancer.

• #71

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The aim is to not only improve survival rates when compared with current empiric treatment but also to reduce unnecessary side effects from ineffective drugs and provide a more complete diagnosis. […] The mutational profile of cancer reflects the aberrant functioning and processes of the neoplastic cells. […] The presence of these signatures can be used as useful indicators of the primary site of the tumour. […] While the primary site is unknown, CUP can be classified into two subgroups to aid in therapeutic decision making. […] Importantly, patients in whom primary anatomic site is strongly suggested by clinical/pathologic criteria should no longer be considered CUP, and treatment should proceed in accordance with established clinical guidelines for that tumour type. […] An integrated diagnostic report is ideal, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. […] Research and improved understanding of genomic variations driving tumour development is critically important for the development of new drug therapies.

• #72

  https://link.springer.com/article/10.1007/s10555-023-10101-6

  The aim is to not only improve survival rates when compared with current empiric treatment but also to reduce unnecessary side effects from ineffective drugs and provide a more complete diagnosis. […] The mutational profile of cancer reflects the aberrant functioning and processes of the neoplastic cells. […] The presence of these signatures can be used as useful indicators of the primary site of the tumour. […] While the primary site is unknown, CUP can be classified into two subgroups to aid in therapeutic decision making. […] Importantly, patients in whom primary anatomic site is strongly suggested by clinical/pathologic criteria should no longer be considered CUP, and treatment should proceed in accordance with established clinical guidelines for that tumour type. […] An integrated diagnostic report is ideal, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. […] Research and improved understanding of genomic variations driving tumour development is critically important for the development of new drug therapies.

• #73 Molecular Profiling for Cancers of Unknown Primary Origin

  https://accrue-health.com/web/public/brands/medicalpolicy/external-policies/molecular-profiling-for-cancers-of-unknown-primary-origin/

  Although the true tissue of origin may not be identifiable in any given case, recent evidence suggests it may be useful to provide site-specific treatment based on tumor type (J. Hainsworth F. Greco, 2023). […] The authors concluded that mutations of relevant driver genes were present in vast majority of CUP tumors and that these genes may carry impact on prognosis and targeted therapy (Loffler et al., 2016). […] The authors concluded that their results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers (Groschel et al., 2016). […] The authors concluded that the clinical benefit of using molecular profiling to guide treatment decisions in CUP remains to be determined. The NCCN also states that currently, there is no evidence of improved outcomes with the use of site-specific therapy guided by molecular testing results in patients with CUP (NCCN, 2024).

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