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PubMed2005

Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1.

BACKGROUND: Cancer of unknown primary remains a mallignancy of elusive biology and grim prognosis that lacks effective therapeutic options. We investigated angiogenesis in cancer of unknown primary to expand our knowledge on the biology of these tumors and identify potential therapeutic targets. METHODS: Paraffin embedded archival material from 81 patients diagnosed with CUP was used. Tumor histology was adenocarcinoma (77%), undifferentiated carcinoma (18%) and squamous cell carcinoma (5%). The tissue expression of CD34, VEGF and TSP-1 was assessed immunohistochemically by use of specific monoclonal antibodies and was analyzed against clinicopathological data. RESULTS: VEGF expression was detected in all cases and was strong in 83%. Stromal expression of TSP-1 was seen in 80% of cases and was strong in 20%. The expression of both proteins was not associated with any clinical or pathological parameters. Tumor MVD was higher in tumors classified as unfavorable compared to more favorable and was positively associated with VEGF and negatively with TSP-1. CONCLUSION: Angiogenesis is very active and expression of VEGF is almost universal in cancers of unknown primary. These findings support the clinical investigation of VEGF targeted therapy in this clinical setting.

Adenocarcinoma↗
PubMed2006

Cancer of unknown primary site: review of consecutive cases at the National Cancer Center Hospital of Japan.

BACKGROUND: Cancer of unknown primary (CUP) is not a rare clinical entity, accounting for 3%-5% of all solid malignancies. METHODS: We retrospectively reviewed 86 (38 male/48 female) patients with a diagnosis of CUP (exclusive of female patients with adenocarcinoma involving the axillary lymph nodes alone and patients with squamous cell carcinoma of the cervical lymph nodes) who were referred to the National Cancer Center Hospital between April 1996 and October 2002. RESULTS: The median interval between the first visit to a local community hospital and referral to our hospital was 1 month (range, 1 to 45 months). The histological diagnosis was adenocarcinoma in 61 patients (71%), poorly differentiated carcinoma in 18 patients (21%), and squamous cell carcinoma in 4 patients (5%). Twenty-three female patients had peritoneal carcinomatosis of adenocarcinoma. Seventy-eight patients (91%) received platinum-containing chemotherapy. Sixty-one of the 86 patients (71%) were categorized as a subgroup of CUP without a specific therapy, and 55 of these 61 patients (90%) received platinum-containing regimens. The median survivals of all 86 patients and the 61 patients in the subgroup without a specific therapy in this series were 13 months and 11 months, respectively. CONCLUSION: In this series, the survival of the patients in the CUP subgroup without a specific therapy did not seem worse than that in previous reports. Empirical chemotherapy with platinum-containing regimens may benefit some CUP patients in a subgroup without a specific chemotherapy.

Adenocarcinoma↗
PubMed2003

Bilateral synchronous tonsillar carcinoma in cervical cancer of unknown primary site (CUPS).

In addition to panendoscopy and imaging for staging, ipsilateral tonsillectomy is a standard procedure in the search for the primary tumor in cervical cancer of unknown primary site (CUPS). It is not clear from the literature, whether bilateral tonsillectomy has been established as the standard procedure in cancer of unknown primary origin. A bilateral synchronous tonsillar carcinoma has thus far only been described three times in the literature. We report on a case of CUPS in which a bilateral tonsillar carcinoma was detected after bilateral tonsillectomy. We also discuss the inclusion of bilateral tonsillectomy as a standard procedure in the search for primary malignancies. To diagnose and adequately treat a bilateral synchronous tonsillar carcinoma without losing time, we recommend bilateral tonsillectomy as a standard procedure in cervical CUPS.

Adult↗
PubMed2002

Tumor markers in metastatic disease from cancer of unknown primary origin.

BACKGROUND: About 5-10% of cancer patients suffer from cancer of unknown primary (CUP). Sophisticated diagnostic techniques have not improved diagnostic efficacy for these patients. The aim of our analysis was to evaluate serum levels of four tumor markers and to relate them to the histology, number, and sites of metastases, the response to chemotherapy, and survival. MATERIAL/METHODS: Blood samples from 46 patients with CUP were assayed for CEA, CA 19-9, CA 15-3 and CA 125. Specific IMx tumor marker assays (Abbott) were used to measure tumor marker quantities. RESULTS: No significant differences were detected between the mean levels of all markers for the two histological types (adenocarcinoma vs. undifferentiated carcinoma). The comparison of tumor marker values in patients with one metastatic location to those with two or more showed no significant differences. We found no differences in marker values between patients with disease sites in the thorax vs. those with abdominal metastases. The comparison of marker negative, CEA positive and non-CEA positive patients failed to reveal significant differences in response rate. The comparison of CEA positive and marker negative patients showed significant differences in survival (log-rank, p=0.02). CONCLUSIONS: Our results suggest that patients with CUP have a nonspecific overexpression of serum tumor markers and that routine use of these markers does not offer diagnostic assistance. Nevertheless, the pattern of expression of some biological markers, such as CEA, could have prognostic significance for survival.

Adult↗
PubMed2000

2[F]-fluoro-2-deoxy-D-glucose positron emission tomography is a sensitive tool for the detection of occult primary cancer (carcinoma of unknown primary syndrome) with head and neck lymph node manifestation.

BACKGROUND: The neck lymph nodes are a common site of metastases from carcinoma of unknown primary (CUP syndrome). 2[(18) F]-fluoro-2-deoxy-D-glucose positron emission tomography (18-FDG-PET) has been shown to be a sensitive tool for detecting primary malignant lesions as well as metastatic spread. We have prospectively investigated the sensitivity of 18-FDG-PET in detecting occult primary carcinomas with manifestation in the head and neck lymph nodes. METHODS: From May 1994 to July 1998, in 723 patients a cancer of the head and neck was diagnosed at the University of Cologne ENT outpatient clinic. The routinely performed staging procedures were chest radiography; full blood count; cervical and liver ultrasound; endoscopy of the nasopharynx, oropharynx, hypopharynx, larynx, and esophagus; and laboratory analyses. After the staging workup, in 27 of 723 patients (3.7%) CUP syndrome had to be presumed because the primary cancer could not be detected. In these patients 18-FDG-PET was performed, and images were reconstructed with a transmission-emission fusion technique. RESULTS: In 7 of 27 patients (26%) 18-FDG-PET revealed an unknown primary: in 2 a bronchial carcinoma, in 2 a nasopharyngeal carcinoma, in 1 a squamous cell carcinoma of the parotid gland, in 1 a squamous cell carcinoma of the hypopharynx, and in 1 a carcinoma of the tonsil. In 4 of 7 patients the occult primary tumor was removed surgically. In 8 of 27 patients therapeutic strategy was changed as a result of the 18-FDG-PET findings. CONCLUSION: 18-FDG-PET should be performed in all patients with CUP syndrome after conventional diagnostic workup fails to identify the primary.

Adenocarcinoma↗
PubMed1986

An analysis of 1539 patients with cancer of unknown primary site.

A retrospective review of 1539 patients with cancer of unknown primary site seen at Yale-New Haven Hospital from 1922 to 1981 was performed. Information was obtained from the Tumor Registry. The method of diagnosis, patient characteristics, year of diagnosis, histologic features, treatment received, and survival were analyzed. The most common cell type was adenocarcinoma. Survival overall was poor, with a median survival of 5 months for the entire group. Age and year of diagnosis did not appear to significantly influence survival. Closer examination of a small subset of those patients with squamous cell carcinoma revealed a very high male:female ratio, possibly related to tobacco and alcohol abuse. Nearly 9% of these patients were found to have a history of one or more unrelated malignancies.

Adenocarcinoma↗
PubMed2006

[FDG-PET in localization of cancers of unknown primary origin].

FDG-PET can be successful in localizing the primary cancer when a metastasis is discovered but no primary tumor can be identified (cancer of unknown primary, or CUP) by physical examination, laboratory testing (for tumor markers, for example) or conventional imaging. The greatest number of PET studies in CUP concern secondary lesions in cervical lymph nodes, and PET is an established clinical use (highest ranking, 1A) according to the 3rd German Consensus Conference and an "option" in the French Standards, Options, and Recommendations. Success rates range from 30% to 50% in most studies using PET; a higher rate was reported recently with PET/CT. FDG-PET should be performed sufficiently early in cases of neurological paraneoplastic syndrome, because established lesions become irreversible. Identification of the antibody present helps to specify the organ and FDG-PET can then localize the lesion; together these techniques make it possible to perform curative surgery even when the primary tumor is not visible. The success rate is somewhat lower than in cases of metastasis, around 35%. The clinical utility of PET in other paraneoplastic syndromes has not yet been sufficiently studied, but these conditions are rare. It is precisely in cases with a kind of 'orphan' indication that FDG PET should be considered, as an effective "problem solver".

Fluorodeoxyglucose F18↗
PubMed1996

[Metastatic cancers of unknown primary site].

It is relatively common to observe metastatic cancer of unknown origin. In approximately 20% of the cases, the primary cancer is later identified during the lifetime of the patient. In others, even necropsy does not reveal the origin. The most frequently identified origins are pancreas or bronchogenic cancer. Initially search is guided by the pathology report of the tumor: well-differentiated adenocarcinoma (60% of the cases), squamous cell cancer (5-10% of the cases), undifferentiated cancer (1/3 of the cases). Immunoperoxydase tumor staining is indispensable to detect specific tumors (1/5 of the cases). Subgroups of adenocarcinomas have been distinguished as for squamous cell carcinoma of unknown origin allowing specific treatment and better results. Recent reports on undifferentiated cancers have demonstrated their increased sensitivity to cisplatin-based chemotherapy. Prognosis remains poor, nevertheless, mean survival does reach approximately one year. Progress has been especially achieved in individualized groups. Chemotherapy remains the basic treatment.

Adenocarcinoma↗
PubMed2026

Cancer of unknown primary: the evolution of tissue of origin identification in the artificial intelligence era.

Cancer of Unknown Primary (CUP) presents substantial diagnostic and therapeutic challenges owing to its heterogeneous nature and the absence of an identifiable primary tumor site. This review provides a structured search of the pathogenesis, epidemiological characteristics, and limitations of traditional diagnostic and therapeutic approaches for CUP, with an emphasis on the evolution of Tissue of Origin (TOO) identification techniques. Recent advances in precision medicine have accelerated the development of machine learning-based TOO identification tools, representing a paradigm shift in CUP diagnostics. Deep learning (DL) algorithms that integrate multi-omics data (such as genomics and transcriptomics) with clinical features have markedly enhanced the accuracy of tracing tumor origin, and artificial intelligence (AI) driven TOO models are increasingly being incorporated into clinical practice, offering new insights for pathological diagnosis, treatment selection, and prognostic evaluation. Nevertheless, several challenges remain, including issues of data standardization, model generalizability, and interpretability. Ethical considerations related to data privacy, algorithmic fairness, and clinical implementation also warrant careful attention. Future research should focus on establishing standardized multi-center databases, developing more interpretable AI models, and fostering multidisciplinary collaborative strategies for CUP management. Through continued refinement of technical solutions and regulatory guidelines, TOO identification is anticipated to progress from research to routine clinical application, ultimately supporting precise and personalized care for patients with CUP.

Artificial intelligence↗
PubMed2003

PET with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) in patients with cancer of unknown primary (CUP): influence on patients' diagnostic and therapeutic management.

25 patients with cancer of unknown primary (CUP) were studied using PET-FDG. Whole-body-PET scans were performed based on previous morphological information. All patients underwent conventional diagnostic modalities prior to and after the PET-study. True positive results were obtained in 12/25 patients (48%) and the primary identified by PET was confirmed by further procedures. True negative results were obtained in 8/25 patients (32%) and no primary tumor was found by PET or other clinical investigations. False positive results were obtained in 5/25 patients (20%). No false negative results were obtained. In 11 patients having CT compared with PET the primary tumor was exclusively localized by PET in 8 patients (73%) and also by CT in 3 patients (27%); CT was unable to identify the tumor in 8/11 patients detected by PET. PET affected management and directed treatment in 11/25 patients (44%). The sensitivity of PET-FDG was 100%, specificity 61%. These observations demonstrate that PET-FDG is a highly sensitive method to detect CUP. Correctly classified patients in an early stage of disease may lead to benefit from a more targeted therapy with prolonged survival time. In cases of advanced disease PET might not decisively influence survival time.

Adult↗
PubMed1999

[Four cases of cancer of unknown primary site that manifested as mediastinal metastatic lesions].

We encountered 4 patients with cancers of unknown primary sites that were manifested by mediastinal lesions. Patient 1 was a 58-year-old man with enlarged superior mediastinal lymph nodes. An exploratory thoracotomy yielded a diagnosis of lymph node metastasis of poorly differentiated adenocarcinoma. The patient was treated with chemotherapy and radiation therapy. Patient 2 was a 68-year-old man with a tumor in the right superior mediastinum. A total resection of the tumor was performed through a thoracotomy. The diagnosis was lymph node metastasis of squamous cell carcinoma, and treatment consisted of irradiation. A tumor shadow in the right upper lobe appeared 14 months after the thoracotomy, and was considered to be a primary lesion requiring a right pneumonectomy. The patient died of hepatic metastasis 6 months after the second operation. Patient 3 was a 59-year-old man with mediastinal and hilar lymph node swelling. Mediastinoscopic findings resulted in a diagnosis of squamous cell carcinoma. Because of the patient's insistence, only radiation therapy was performed. Patient 4 was a 65-year-old woman with a tumor in the right superior mediastinum who underwent a median sternotomy for total resection of the tumor. The pathological findings were strongly suggestive of metastasis of clear cell carcinoma. Patients 1, 3, and 4 were alive 33, 24, and 51 months, respectively, after their initial operation, without detectable primary sites. Patient 2 was considered to have had T 0 N 2 lung cancer.

Adenocarcinoma↗
PubMed2001

Treatable subsets in cancer of unknown primary origin.

The purpose of this study was to investigate the treatable subsets in cancer of unknown primary origin (CUP). Fifty patients (27 males and 23 females; median age, 53 years) with CUP diagnosed between April 1992 and June 1999 were analyzed retrospectively. Of the 50 patients, 39 received chemotherapy: platinum-based in 31, non-platinum-based in 4, and clinical trials of new agents in 4. Of the 39 patients, 13 (33.3%; 95% confidence interval: 19.1 - 50.2%) showed objective responses, with 4 complete responders. Patients with poorly differentiated carcinomas in whom beta-subunit of human chorionic gonadotropin (beta-HCG) was elevated more than 10 mIU / ml and female patients with peritoneal adenocarcinomatosis achieved high response rates (83.3% and 80%, respectively) with platinum-based chemotherapy, as compared with only a 15.3% response rate in the remaining patients. Platinum-based chemotherapy provided promising results in patients with poorly differentiated carcinomas and in female patients with peritoneal adenocarcinomatosis. Significantly elevated serum levels of beta-HCG in patients with poorly differentiated carcinoma might predict a better response to platinum-based chemotherapy. However, the investigation of novel chemotherapeutic approaches is warranted for other groups of patients with CUP.

Adenocarcinoma↗
PubMed1993

Cancer of unknown primary. A retrospective study based on 109 patients.

Cases of 109 patients with metastases from cancer of unknown primary (CUP) were retrospectively analyzed. The highest survival rates were observed in patients with high performance status and metastases limited to the cervical lymph nodes. With other metastatic presentations, the survival was generally very short. Tumor markers did not demonstrate diagnostic value. The primary tumor was revealed by autopsy in 43 of 64 cases. Lungs were the most common primary site, followed by the gastrointestinal tract. Extensive clinical investigations during the initial diagnostic period were, as a rule, fruitless. Patients with CUP require efficacious treatment, but need to be investigated with adequate measures.

Adult↗
PubMed1991

[Metastases from cancers of unknown primary site. Data from 302 autopsies].

The autopsies of 302 patients who had metastases from cancers of unknown primary site were studied. In two-thirds of the cases the metastases were located in the lymph nodes, the lungs and the bones. The primary tumour was found in 82 patients when still alive (27 percent) and in 173 patients (57 percent) at autopsy. It could not be identified in 16 percent of the cases. The primary tumours most often discovered were in the pancreas (26.5 percent), the lungs (17.2 percent), the kidneys (4.6 percent) and the colorectal bowel (3.6 percent). On the whole, the paraclinical examinations performed for diagnostic purposes had been disappointing. The survival rate was the same whether or not the primary tumour had been identified. The number of inaugural metastases seems to be a major prognostic factor. These highly progressive tumours must represent a very distinct clinical and biological neoplastic entity. A simple approach and a unicist practical management are suggested.

Adolescent↗
PubMed2003

Brain metastases in patients with cancer of unknown primary.

Between January 1985 and December 2000, 916 patients with brain metastases were treated with whole brain radiation therapy (WBRT) at the Department of Radiotherapy, University Hospital Freiburg. In 47 patients, a primary tumor could not be identified (cancer of unknown primary (CUP)). Sixteen patients had a solitary brain metastasis, 31 patients presented with multiple brain metastases. Surgical resection was performed in 15 patients, biopsy alone in 12 patients. WBRT was applied with daily fractions of 2 or 3 Gy to a total dose of 50 or 30 Gy, respectively. According to the recursive partitioning analysis (RPA) classes of the Radiation Therapy Oncology Group for patients with brain metastases none of the patients met the criteria for Class I, 23 for Class II, and 24 for Class III. The median overall survival (OS) for all patients with brain metastases (n = 916) was 3.4 and 4.8 months for patients with CUP (p = 0.45). In patients with CUP (n = 47) the median OS for patients with a single brain metastasis was 7.3 versus 3.9 months for patients with multiple brain metastases (p = 0.05). Median OS for patients with a Karnofsky performance status (KPS) > or = 70 was 6.3 months versus 3.2 months for KPS < 70 (p = 0.01). At multivariate analysis performance status and resection status could be identified as independent prognostic factors for the OS.

Adult↗
PubMed2006

[Cutaneous metastases from adenocarcinoma of unknown primary site].

Metastatic cancer of unknown primary site appears in 5-10% of oncologic patients. The primary tumor is usually discovered at autopsy and only in 27% of patients alive. Metastases from cancer of unknown primary site may be located in the skin and subcutaneous tissue and it is the dermatologist the first in evaluating these patients. We present a case of cutanoeus metastases from moderately-differentiated adenocarcinoma of unknown primary site. The immunohistochemical study revealed positive staining for CEA and negative staining for PSA. The primary tumor could not be identified in spite of the imaging and endoscopic studies performed. Based on these studies we excluded a colorectal or prostatic origin and considered a pancreatic adencarcinoma as the possible primary tumor. Even though a minority of these patients will have a curable disease, the appropriate use of pathological diagnosis and selected imaging studies for an optimal management of patients with a tumor of unknown primary site should not be ignored.

Abdominal Neoplasms↗
PubMed1988

[A cancer of unknown primary site with diffuse metastasis to the bone marrow treated effectively with FAM combination chemotherapy].

A patient with cancer of unknown primary site suffering from diffuse bone marrow metastasis and DIC, was treated with FAM (5-fluorouracil, adriamycin and mitomycin C) combination chemotherapy. She was a 58-year-old housewife. Bone marrow biopsy revealed that her marrow tissue was completely replaced by cancer cells, and bone scintigraphy showed diffuse bone marrow metastasis in all the vertebrae, sternum, pelvic bones and skull. After 5 months administration of 3 courses of FAM therapy, the cancer cells were completely eradicated in the bone marrow upon biopsy taken at almost the same position as the previous one. The values of CEA, CA 19-9 and CA 125 were normalized, suggesting that this therapy was very effective.

Anemia, Myelophthisic↗
PubMed2004

A phase II study of paclitaxel plus cisplatin chemotherapy in an unfavourable group of patients with cancer of unknown primary site.

OBJECTIVE: We evaluated the efficacy and toxicity of combined paclitaxel and cisplatin chemotherapy in patients with cancer of unknown primary site (CUP). Efficacy was evaluated in terms of response rate, progression-free survival and overall survival. METHODS: Thirty-seven patients with CUP were enrolled between January 2001 and September 2003 at Korea Cancer Center Hospital. The patients received 21-day cycles of paclitaxel (175 mg/m(2) i.v.) with cisplatin (60 mg/m(2) i.v.) given on the first day. RESULTS: Of the 37 patients, 31 had adenocarcinoma subtypes. The overall response rate of 26 patients with measurable lesions was 42% [95% confidence interval (CI) 23-61%]. Stable disease was seen in six patients and progressive disease in nine. Median time to progression was 4 months (95% CI 1.3-6.8). Median overall survival was 11 months (95% CI 8.3-13.5). The major toxicities were neuropathy and neutropenia. Grade 4 neutropenia occurred in 10 patients, but febrile neutropenia was seen in four. CONCLUSIONS: This combined paclitaxel and cisplatin regimen was well tolerated with an encouraging level of effectiveness for patients with CUP.

Adenocarcinoma↗