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Cancer of Unknown Primary

Cancer of Unknown Primary (CUP) makes up about 3% of all people diagnosed with cancer. CUP is where cancer is found to have spread to secondary site(s) but routine testing could not find where the cancer started (the primary site). Even with specialised testing the primary site still cannot be identified for many people. Sometimes this may be because the primary tumuor is still very small, or the primary tumour has shrunk or totally disappeared, or the primary tumour was removed during previous surgery for another condition. The most frequent type of CUP are carcinomas (cancer starting in epithelial cells), often the cells are poorly differentiated (hard to tell the specific cell type under the microscope), making it hard to identify the specific part of the body where the cancer started.

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    MeSH term: Neoplasms, Unknown Primary
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Sivars L, Landin D, Grün N, et al.
Validation of Human Papillomavirus as a Favourable Prognostic Marker and Analysis of CD8(+) Tumour-infiltrating Lymphocytes and Other Biomarkers in Cancer of Unknown Primary in the Head and Neck Region.
Anticancer Res. 2017; 37(2):665-673 [PubMed] Related Publications
BACKGROUND: Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed.
MATERIALS AND METHODS: A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8(+)) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC.
RESULTS: HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8(+) TIL counts indicated favourable prognosis.
CONCLUSION: HPV status is useful for the management of patients with HNCUP and the role of CD8(+) TILs should be further explored.

Clemente N, Alessandrini L, Vaccher E, et al.
Multiple preinvasive and invasive HPV-related lesions of the anogenital tract in a female patient with HIV infection: A case report.
Medicine (Baltimore). 2017; 96(4):e5948 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Patients with human immunodeficiency virus (HIV) infection have been shown to be at increased risk for high-risk human papillomavirus (HR-HPV) infection of the anogenital tract. Furthermore, in the last decades, the introduction of highly active antiretroviral therapy (HAART) has increased the longevity of these patients who now live long enough to develop HPV-related cancers; hence, the impact of HPV infection on HIV-positive patients is of increasing concern.
PATIENT CONCERNS: We reported the case of an HIV-positive female patient on HAART with a good virological and immunological response and with a long history of HPV-related intraepithelial and invasive lesions of the anogenital tract.
DIAGNOSES: From 1996 to 2016, this patient was diagnosed with a high grade cervical intraepithelial neoplasia; a HR-HPV positive inguinal lymph node metastasis from clinically undetectable primary squamous cell carcinoma; a HPV-related vulvar high-grade squamous intraepithelial lesion and an invasive squamous cell carcinoma of the anus.
INTERVENTIONS: All the intraepithelial and invasive lesions detected were properly treated, and subsequent follow up visits with gynecologic examination, anoscopy, pap smear and anal cytology were performed.
OUTCOMES: After a recurrence of the anal cancer and a subsequent salvage surgery with abdominoperineal resection, at the last available follow up visit no sign of disease recurrence was found.
LESSONS: This case stresses the importance of an accurate multidisciplinary follow-up in HIV-positive patients, including not only the routine medical, immunological, and virological evaluation, but also a periodical complete examination of the anogenital tract with cervicovaginal and anal cytology, colposcopy, high resolution anoscopy, and vulvar examination.

Arosio AD, Pignataro L, Gaini RM, Garavello W
Neck lymph node metastases from unknown primary.
Cancer Treat Rev. 2017; 53:1-9 [PubMed] Related Publications
Metastatic cervical carcinoma from unknown primary is a metastatic disease in the lymph nodes of the neck without any evidence of a primary tumour after appropriate investigation. The condition is rare and definite evidence is lacking for both diagnosis and treatment. In this review of the literature, we tried to draw some clinical indications based on the few available studies. We ultimately came to the following conclusions: (1) a thorough and accurate diagnostic work-up should be systematically offered. It includes accurate inspection with fibroscopy, CT or MRI, fine needle aspiration, panendoscopy and positron emission tomography, (2) Patients with low-volume neck disease, N1 and N2a stage and without extracapsular extension on histopathological examination should receive single modality treatment. Radiotherapy and surgery may be similarly effective but, if possible, surgery (excisional biopsy, neck dissection and tonsillectomy) should be favoured because it consents a more precise staging, (3) patients with more advanced conditions require combined treatment in the form of either resection followed by adjuvant radiation (±chemotherapy) or primary chemoradiation (±post-therapy neck dissection).

Mackenzie K, Watson M, Jankowska P, et al.
Investigation and management of the unknown primary with metastatic neck disease: United Kingdom National Multidisciplinary Guidelines.
J Laryngol Otol. 2016; 130(S2):S170-S175 [PubMed] Free Access to Full Article Related Publications
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the evidence base pertaining to the management of metastatic neck disease in the setting of an unknown primary and provides recommendations on the work up and management for this group of patients receiving cancer care. Recommendations • All patients presenting with confirmed cervical lymph node metastatic squamous cell carcinoma and no apparent primary site should undergo: ○ Positron emission tomography-computed tomography whole-body scan. (R) ○ Panendoscopy and directed biopsies. (R) ○ Bilateral tonsillectomy. (R) • Tongue base mucosectomy can be offered if facilities and expertise exists. (G) • Concomitant chemotherapy with radiation should be considered in patients with an unknown primary. (R) • Concomitant chemotherapy with radiation should be offered to suitable patients in the post-operative setting, where indicated. (R) • Neo-adjuvant chemotherapy can be used in gross 'unresectable' disease. (R) • Patients should be followed up at least two months in the first two years and three to six months in the subsequent years. (G) • Patients should be followed up to a minimum of five years with a prolonged follow up for selected patients. (G) • Positron emission tomography-computed tomography scan at three to four months after treatment is a useful follow-up strategy for patients treated by chemoradiation therapy. (R).

Gődény M, Lengyel Z, Polony G, et al.
Impact of 3T multiparametric MRI and FDG-PET-CT in the evaluation of occult primary cancer with cervical node metastasis.
Cancer Imaging. 2016; 16(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to determine the ability of multimodal evaluation with multiparametric 3T-MRI (MPMRI) and positron emission tomography - computed tomography (PET/CT) to detect cancer of unknown primary origin (CUP) with neck lymph node (LN) metastasis.
METHODS: The study group comprised 38 retrospectively analysed consecutive patients with LN metastasis in the head and neck (HN) region without known primary tumours (PTs). Statistical values of 3T-MRI and of FDG-PET/CT scans were evaluated.
RESULTS: Of the 38 CUPs, conventional native T1-, T2-weighted and STIR sequences detected 6 PTs. Native sequences plus diffusion-weighted imaging (DWI) found 14-, and with fat suppression contrast-enhanced T1-weighted measurement as well as with the complex MPMRI found 15 primaries and with PET/CT 17 CUPs could be evaluated, respectively. The detection rates were 15.8, 36.8, 39.5, 39.5 and 44.7 % for conventional native MRI, native plus DWI, native with contrast-enhanced MRI (CE-MRI), for MPMRI, and for PET/CT, respectively. The overall detection rate proved by histology was 47.4 %. PET/CT provided the highest sensitivity (Sv: 94.4 %) but a lower specificity (Sp: 65.0 %), using MPMRI (Sv: 88.2 %) the specificity increased to 71.4 %. DWIincreased specificity of the native sequences (Sp: 76.2 %). Conventional native sequences plus DWI as well as 3T-MPMRI and PET/CT were same accurate (Acc: 79.0 %) and had similar likelihood ratio (LR: 3.42, 3.03 and 2.62) in detecting unknown PT sites.
CONCLUSIONS: The accuracy of FDG-PET/CT and MPMRI in case of CUP in finding the primary cancer in the neck regions is identical. While using PET/CT whole body information can be obtained in one examination. MPMRI shows the local soft tissue status more accurately. In cases of CUP PET/CT should be the first method of choice if it is available. MPMRI can clarify the exact primary tumor stage, and it can be advantageous in clarifying the prognostic factors, which is necessary in case of advanced tumor stage and when surgery is under consideration. In case low N stage is likely after the clinical examination and wait and see policy can be considered, MPMRI is recommended, and in this case the significance the of radiation free MPMRI is increasing.

Çoban A, Gündoğdu G, Poyraz M, et al.
NMDA receptor encephalitis with cancer of unknown primary origin.
Tumori. 2016; 102(Suppl. 2) [PubMed] Related Publications
PURPOSE: N-methyl-D-aspartate receptor (NMDAR) encephalitis may present as a paraneoplastic syndrome in young women and is often associated with ovarian teratoma.
METHODS: We report 2 male cases of NMDAR encephalitis presenting with metastatic cancer of unknown primary origin.
RESULTS: Both patients showed cognitive dysfunction as well as other neurological symptoms, slow waves on EEG, and NMDAR antibodies in sera and CSF. Symptoms were effectively treated by pulse steroid and intravenous immunoglobulin treatment. The patients developed metastatic small cell neuroendocrine carcinoma of the parotid gland and inguinal metastatic squamous cell cancer shortly after their neurological episodes. Follow-up PET studies showed small cell lung cancer in the first patient while no primary origin could be found in the second patient.
CONLUSIONS: Our cases imply that NMDAR encephalitis may present with metastatic cancers that display slow progression rates and occur after encephalitis attacks.

Ruhlmann V, Ruhlmann M, Bellendorf A, et al.
Hybrid imaging for detection of carcinoma of unknown primary: A preliminary comparison trial of whole-body PET/MRI versus PET/CT.
Eur J Radiol. 2016; 85(11):1941-1947 [PubMed] Related Publications
PURPOSE: The aim of this study is to evaluate and compare the diagnostic potential of integrated whole-body [18F]FDG-PET/MRI to [18F]FDG-PET/CT for detection of a potential primary cancer and metastases in patients suspected for cancer of unknown primary (CUP).
METHODS: A total of 20 patients (15 male, 5 female, age 53±13 years) suspect for CUP underwent a dedicated head and neck & whole-body [18F]FDG-PET/CT (Biograph mCT 128, Siemens Healthcare) and a subsequent simultaneous [18F]FDG-PET/MRI examination (Biograph mMR, Siemens Healthcare). Two readers rated the datasets (PET/CT; PET/MRI) regarding the detection of the primary cancer and metastases, lesion conspicuity (4-point ordinal scale) and diagnostic confidence (3-point ordinal scale). PET analysis comprised the assessment of maximum standardized uptake values (SUVmax) of all PET-positive lesions using volume of interest (VOI) analysis derived from the PET/CT and PET/MR datasets. All available data considering histology and imaging including prior and clinical follow-up examinations served as reference standard. Statistical analysis included comparison of mean values using Mann-Whitney U test and correlation of SUVmax using Pearson's correlation.
RESULTS: In 14 out of 20 patients 49 malignant lesions were present. The primary cancer could be correctly identified in 11/20 patients with both PET/CT and PET/MRI. PET/CT enabled the detection of a total 38 metastases, PET/MR respectively of 37 metastases (one lung metastasis <5mm was missed). PET/CT and PET/MRI showed comparably high lesion conspicuity (2.6±0.6 each), with superior assessment of cervical lesions in PET/MRI and an indicated superior assessment of pulmonary lesions in PET/CT. Diagnostic confidence was rated comparably high in PET/CT and PET/MRI (2.7±0.5 each). The mean values of SUVmax of all PET-positive lesions (PET/MRT 7.9±4.2 vs. PET/CT 7.2±3.5) showed a strong positive correlation between the SUVs derived from both hybrid imaging systems (Pearson's correlation r=0.927).
CONCLUSIONS: Both hybrid imaging techniques provide a comparable diagnostic ability for detection of primary cancer and metastases in patients with CUP, with comparably high lesion conspicuity and diagnostic confidence, offering superior assessment of cervical lesions in PET/MRI and potentially of pulmonary lesions in PET/CT. Furthermore, due to the significantly lower dose of ionizing radiation, PET/MRI may serve as a powerful alternative to PET/CT, particularly for therapy monitoring and/or surveillance considering the long-term cumulative dose.

Drouet C, Morel O, Boulahdour H
Bilateral Huge Incidentalomas of Isolated Adrenal Metastases From Unknown Primary Melanoma Revealed by 18F-FDG PET/CT.
Clin Nucl Med. 2017; 42(1):e51-e53 [PubMed] Related Publications
FDG PET/CT has high sensitivity and specificity for the detection of distant metastases from cutaneous melanoma. Imaging is recommended for patients with clinical suspicion of metastasis and should be considered for those with confirmed sentinel lymph node metastasis. Metastatic melanoma bears a poor prognosis. Only a complete resection improves survival, which explains the need to detect potentially unresectable disease, and most metastatic patients are ineligible for a curative surgical procedure. Here, FDG PET/CT demonstrated isolated bilateral adrenal metastases from melanoma of unknown primary. The patient underwent curative surgery, with no sign of recurrence at 48 months after surgery.

Tomic K, Westerberg M, Robinson D, et al.
Proportion and characteristics of men with unknown risk category in the National Prostate Cancer Register of Sweden.
Acta Oncol. 2016; 55(12):1461-1466 [PubMed] Related Publications
BACKGROUND: Knowledge on missing data in a clinical cancer register is important to assess the validity of research results. For analysis of prostate cancer (Pca), risk category, a composite variable based on serum levels of prostate specific antigen (PSA), stage, and Gleason score, is crucial for treatment decisions and a strong determinant of outcome. The aim of this study was to assess the proportion and characteristics of men in the National Prostate Cancer Register (NPCR) of Sweden with unknown risk category.
MATERIAL AND METHODS: Men diagnosed with Pca between 1998 and 2012 registered in NPCR with known or unknown risk category were compared with respect to age, socioeconomic factors, comorbidity, cancer characteristics, cancer treatment, and mortality from Pca and other causes.
RESULTS: In total, 3315 of 129 391 (3%) men had unknown risk category. Compared to other men in NPCR, these men more often had a concomitant bladder cancer diagnosis, 19% versus 1%, diagnosis of benign prostatic hyperplasia 31% versus 5%, received unspecified Pca treatment 16% versus 3%, had higher comorbidity, Charlson Comorbidity Index 2 or higher, 34% versus 13%, and had lower Pca mortality 12% versus 30%, but similar mortality from other causes.
CONCLUSION: Men with unknown risk category were rare in NPCR but distinctly different from other men in NPCR in many aspects including higher comorbidity and lower Pca mortality.

Dale E, Moan JM, Osnes TA, Bogsrud TV
Cervical lymph node metastases of squamous cell carcinoma of unknown origin: the diagnostic value of FDG PET/CT and clinical outcome.
Eur Arch Otorhinolaryngol. 2017; 274(2):1015-1019 [PubMed] Related Publications
FDG PET/CT is perceived as a valuable diagnostic tool in addition to the standard diagnostic workup for patients with isolated neck lymph nodes of squamous cell carcinoma of unknown primary (SCCUP). For patients with SCCUP intended for primary radiotherapy, we hypothesize that the previously reported FDG PET/CT detection rates are too high. From 2008 to 2015, 30 SCCUP patients were examined with FDG PET/CT. The objective of the FDG PET/CT examination was twofold: (1) improve the radiotherapy target definition, and (2) identify the primary cancer. Before the FDG PET/CT, the patients had been through a standard workup consisting of CT of the neck and chest, examination with flexible endoscopy with patient awake, panendoscopy and examination under general anesthesia, tonsillectomy and sometimes blind sampling biopsies, and MRI (floor of the mouth). All FDG PET/CTs were performed applying a flat table, head support and fixation mask as part of the radiotherapy treatment planning. Diagnostic CT with contrast was an integrated part of the PET/CT examination. Only 1/30 patients (cancer of the vallecula) had their primary cancer detected by FDG PET/CT. In addition, a non-biopsied patient with high uptake in the ipsilateral palatine tonsil was included, giving a detection rate of ≤7 % (95 % CI 2-21 %). In this retrospective study, we found that the FDG PET/CT detection rate of the primary for SCCUP patients is lower than previously reported. It is questionable whether FDG PET/CT is necessary for these patients when improved, advanced workup is available.

Ma Y, Xu W, Bai R, et al.
Volume-based predictive biomarkers of sequential FDG-PET/CT for sunitinib in cancer of unknown primary: identification of the best benefited patients.
Eur J Nucl Med Mol Imaging. 2017; 44(2):199-205 [PubMed] Related Publications
PURPOSE: To test the performance of sequential (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting survival after sunitinib therapies in patients with cancer of unknown primary (CUP).
METHODS: CUP patients were enrolled for sequential PET/CT scanning for sunitinib and a control group. Univariate and multivariate analysis were applied to test the efficacy of sunitinib therapy in CUP patients. Next, sequential analyses involving PET/CT parameters were performed to identify and validate sensitive PET/CT biomarkers for sunitinib therapy. Finally, time-dependent receiver operating characteristic (TDROC) analyses were performed to compare the predictive accuracy.
RESULTS: Multivariate analysis proved that sunitinib group had significantly improved survival (p < 0.01) as compared to control group. After cycle 2 of therapy, multivariate analysis identified volume-based PET/CT parameters as sensitive biomarkers for sunitinib (p < 0.01). TDROC curves demonstrated whole-body total lesion glycolysis reduction (Δ WTLG) and follow-up WTLG to have good accuracy for efficacy prediction. This evidence was validated after cycle 4 of therapy with the same method.
CONCLUSION: Sunitinib therapy proved effective in treatment of CUP. PET/CT volume-based parameters may help predict outcome of sunitinib therapy, in which Δ WTLG and follow-up WTLG seem to be sensitive biomarkers for sunitinib efficacy. Patients with greater reduction and lower WTLG at follow-up seem to have better survival outcome.

Rapisuwon S, Busam KJ, Parks K, et al.
Discordance Between Cobas BRAF V600 Testing and VE1 Immunohistochemistry in a Melanoma Patient With Bone Marrow Metastases.
Am J Dermatopathol. 2016; 38(9):687-9 [PubMed] Related Publications
False negative result remains an ongoing problem in direct gene sequencing of cancers. It is important to use the appropriate mutation detection method most appropriate to each circumstance and the available tissue. Here, we report a patient with melanoma of unknown primary with metastases to spleen and bone marrow, who was tested negative for Cobas BRAF V600E mutation, whose cancer progressed on antiprogrammed death 1 (PD1) receptor monoclonal antibody therapy. Subsequent VE1 immunohistochemistry was positive for BRAF V600E mutation, and the tumor responded dramatically to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/Mitogen-activated protein kinase inhibitor combination therapy. This demonstrates how alternative BRAF testing methodology could produce results that can influence treatment choice and the outcome.

Uzunoglu S, Erdogan B, Kodaz H, et al.
Unknown primary adenocarcinomas: a single-center experience.
Bosn J Basic Med Sci. 2016; 16(4):292-297 [PubMed] Free Access to Full Article Related Publications
This study aimed to elucidate the clinical and prognostic characteristics of a homogeneous group of patients with cancer of unknown primary (CUP). Between 1999 and 2014, CUP was diagnosed in 159 (1.3%) of 11,742 cancer patients at Trakya University Hospital (Edirne, Turkey). Ninety-seven (61%) of the 159 patients were retrospectively reviewed. Among these, 61 (62.8%) patients with adenocarcinoma were included in this study. The most frequently predicted primary tumor site was the lung (37.7%), and 59% of the patients were smokers. There was a significant relationship between smoking and the lung as a potential primary cancer site (p = 0.042). The most frequent site of metastasis was the liver (60.7%). The median number of metastases per patient was two, but patients with liver metastases had a median of five metastases. The overall median survival time was 7 months. Median survival was significantly longer in patients with a predicted primary site than in patients without the predicted site (7 vs. 6 months, respectively; p = 0.038). When the patients with predicted ovarian and peritoneal tumors were excluded from the comparison, the statistical p value was still close to significant (p = 0.07). Multivariate analysis revealed that smoking, liver metastasis, serum alkaline phosphatase ≥92 U/L, and progression in response to chemotherapy were independent predictors of a poor prognosis. The present study identified several independent prognostic factors in patients with unknown primary adenocarcinomas who received chemotherapy. Smoking, the presence of liver metastasis, and response to chemotherapy were independent risk factors for both progression-free and overall survival.

Ahdallah R, Morse B, Hakam A, Shahzad MM
Pelvic squamous cell carcinoma of unknown primary: a case report and review of the literature.
Eur J Gynaecol Oncol. 2016; 37(3):430-3 [PubMed] Related Publications
Retroperitoneal squamous cell carcinoma (SCC) of unknown primary is very rare with variable survival rates. Standard optimal therapeutic management is not yet established.

Farnebo L, Laurell G, Mäkitie A
A Nordic survey on the management of head and neck CUP.
Acta Otolaryngol. 2016; 136(11):1159-1163 [PubMed] Related Publications
CONCLUSION: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies both between centres within and also between the Nordic countries. This study contributes to a continuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP patients.
OBJECTIVES: The initiative for this study was based on the lack of common guidelines for diagnostic procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a rather homogeneous population.
METHOD: A structured questionnaire was sent to all university hospitals in the five Nordic countries.
RESULTS: Four of the five Nordic countries use either national guidelines or specific protocols when handling HNCUP. The main diagnostic tools are PET-CT, fine needle aspiration, endoscopic evaluation with biopsies, and most often bilateral tonsillectomy. At 21 of 22 university hospitals the treatment decision is made at a multidisciplinary conference. Three of seven Swedish centres use only radiotherapy or chemoradiotherapy to treat N+ HNCUP patients. Robotic surgery for biopsy of the tongue base is beginning to become an alternative to targeted biopsies in Sweden and Finland. Narrow Band Imaging is used only in Finland.

Friedrich RE, Zustin J
Mucoepidermoid Carcinoma - Unknown Primary Affecting the Neck.
Anticancer Res. 2016; 36(6):3169-71 [PubMed] Related Publications
The present report describes therapy and follow-up of a patient who experienced a localized swelling of the neck that proved to be a mucoepidermoid carcinoma. Extensive staging revealed no primary site. Therapy was modified neck dissection followed by external application of chemotherapy combined with fractionated radiotherapy. Over a period of 43 months, the patient has remained free of local tumour growth and distant metastasis. Whereas prognosis of mucoepidermoid carcinoma in general is good, prognosis of patients affected by mucoepidermoid carcinoma with carcinoma of unknown primary is ambiguous.

Romero M, González-Fontal GR, Duarte M, et al.
Small clonal B-cell population in the bone marrow as a possible tool in the diagnosis of occult primary parotid lymphoma.
Colomb Med (Cali). 2016; 47(1):59-62 [PubMed] Free Access to Full Article Related Publications
CASE DESCRIPTION: An 82-years old Hispanic woman with a past medical history significant for pulmonary thromboembolism on oral anticoagulation, rheumatoid arthritis, and hypertension developed a new onset thrombocytopenia.
CLINICAL FINDINGS: Small clonal B-cells populations (SCBP) also known as monoclonal B-cell lymphocytosis was found as part of the workup for an idiopathic thrombocytopenia and lead ultimately to the diagnosis of parotid primary follicular lymphoma coexisting with Warthin tumor involving the bone marrow in a small extent and oncocytic papilloma located in the maxillary sinus.
TREATMENT AND OUTCOME: Patient was treated with Rituximab monotherapy with improvement on her platelet count.
CLINICAL RELEVANCE: Although it is unclear the role of this clonal cells, they may work as a possible diagnostic tool for occult lymphomas. Further prospective studies are needed to confirm this possible association.

Liu M, Chen G, Fu Z, et al.
Occult Mediastinal Yolk Sac Tumor Producing α-Fetoprotein Detected by 18F-FDG PET/CT.
Clin Nucl Med. 2016; 41(7):585-6 [PubMed] Related Publications
Malignant mediastinal yolk sac tumor (YST), especially adult onset, is rare. Herein, we report a case of occult mediastinal YST with α-fetoprotein production revealed by F-FDG PET/CT in a young adult, in which the intense tracer uptake was demonstrated in the anterior mediastinum. This case indicates F-FDG PET/CT may be a useful tool for detecting the occult primaries of YST.

Scott JF, Thompson CL, Vyas R, et al.
Parotid melanoma of unknown primary.
J Cancer Res Clin Oncol. 2016; 142(7):1529-37 [PubMed] Related Publications
PURPOSE: Rarely, melanoma is discovered in the parotid gland without an identifiable primary site. It is not known how patients with parotid melanoma of unknown primary (PMUP) compare to those with a known primary (PMKP). As such, we describe the largest series of patients with PMUP to date and compare them to patients with PMKP.
METHODS: We analyzed cases from three sources: (1) the University Hospitals Case Medical Center pathology database (n = 45), (2) the Surveillance, Epidemiology, and End Results 18 database (n = 33), and (3) a comprehensive literature search (n = 32).
RESULTS: PMUP patients were predominately male and presented at a mean age of 56 years. When compared to PMKP, PMUP cases were more likely to be diagnosed in the parotid parenchyma, present with stage IV disease, and develop distant metastases during follow-up in a shorter amount of time. However, there was no difference in overall survival between patients with PMUP and PMKP presenting with stage-matched disease.
CONCLUSIONS: Overall survival is similar for stage-matched patients with parotid melanoma presenting with an unknown and known primary site.

Gheshmy A, Carrier M
Venous thromboembolism and occult cancer: impact on clinical practice.
Thromb Res. 2016; 140 Suppl 1:S8-11 [PubMed] Related Publications
Unprovoked venous thromboembolism (VTE) can be the first manifestation of cancer. Given this relationship between unprovoked VTE and cancer, it is appealing for clinicians to screen their patients with a first episode of acute unprovoked VTE for a potential occult malignancy. Five different studies have compared a limited (thorough history and physical exam, basic bloodwork) to a more extensive occult cancer screening strategy (e.g. computed tomography, fludeoxyglucose positron emission tomography, etc.). Most of these studies have failed to show that an extensive occult cancer screening strategy diagnoses more occult cancer (including early cancers), misses fewer cancers during follow-up or improves overall and/or cancer-related mortality suggesting that extensive occult cancer screening should not be performed routinely. Therefore, patients with a first unprovoked VTE should undergo a limited cancer screening only and clinicians should ensure that their patients are up to date regarding age- and gender- specific cancer screening (colon, breast, cervix and prostate) as per their national recommendations. Current evidence does not support a net clinical benefit to perform an extensive occult cancer screening on all patients, and a decision to do additional testing should be made on a case by case basis.

Feng Z, Wang S, Huang Y, et al.
A follow-up analysis of positron emission tomography/computed tomography in detecting hidden malignancies at the time of diagnosis of membranous nephropathy.
Oncotarget. 2016; 7(9):9645-51 [PubMed] Free Access to Full Article Related Publications
Membranous nephropathy (MN) is the most common kidney disease reported in a variety of malignant diseases. Search for an occult malignancy in MN has presented special challenges. 124 MN patients with a physical examination not suspicious for cancer underwent screening for an occult malignancy with either 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scanning (n = 49) or conventional screening (n = 75) at the time of diagnosis of MN, and were followed up (median,28 months). 154 patients who refused to undergo any screening were followed up (median, 30 months). In FDG-PET/CT cohort, 5 (10.20%) patients were screened and confirmed as malignancy, in contrast, 1 (1.33%) patient in conventional screening cohort. During follow-up, none of malignancy was detected in FDG-PET/CT cohort, 3(4.05%) patients in conventional screening cohort, and 8(5.19%) patients in no-screening cohort. All 6 cases of cancer were detected at early stages and underwent curative resection, and after the resection, proteinuria decreased. In contrast, 11 cases of cancer detected during follow-up died without any remission of proteinuria. These preliminary data provide the first evidence for a potential cancer surveillance that the malignancy screening either through conventional or by PET-CT at the diagnosis of MN led to an early diagnosis and curative treatment.

Hemminki K, Pavlidis N, Tsilidis KK, et al.
Age-Dependent Metastatic Spread and Survival: Cancer of Unknown Primary as a Model.
Sci Rep. 2016; 6:23725 [PubMed] Free Access to Full Article Related Publications
In order to describe a novel approach for the clinical study of metastases, we provide here age-specific incidence and survival data for cancer of unknown primary (CUP). Metastases in various organs are found at CUP diagnosis, which have implications for prognosis, and we hypothesize similar prognostic implications for metastases found at diagnosis of primary cancers. We identified 33,224 CUP patients from the Swedish Cancer Registry and calculated incidence rates (IRs) for CUP development. Cox proportional hazards regression models were performed to estimate hazard ratios (HRs) for relative survival in CUP patients compared to the general population. In age-group specific analyses, a maximal IR was reached at age 85-89 years, followed by a marked decline to age 90+ (7-fold in men and 3-fold in women). The overall HR for relative survival declined systematically by age. CUP may be applied as an epidemiological age-incidence model for cancer metastases providing evidence in line with autopsy data that the metastatic potential, as shown by the incidence of CUP, appears to weaken markedly at age 85 years, depending on metastatic locations. The relative death rates were highest among young patients, which was probably entirely due to the low death rates in young background population.

Hemminki K, Sundquist K, Sundquist J, et al.
Location of metastases in cancer of unknown primary are not random and signal familial clustering.
Sci Rep. 2016; 6:22891 [PubMed] Free Access to Full Article Related Publications
Cancer of unknown primary (CUP) is a fatal disease diagnosed through metastases. It shows intriguing familial clustering with certain defined primary cancers. Here we examine whether metastatic location in CUP patients is related to primary non-CUP cancers in relatives based on the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP patients defined by metastatic location depending on cancer in their first degree relatives. SIRs for CUP were high in association with liver (3.94), ovarian (3.41), lung (2.43) and colorectal cancers (1.83) in relatives. The SIR was 1.63 for CUP with metastases in the abdomen when a relative was diagnosed with ovarian cancer. CUP with liver metastases associated with liver (1.44) cancer in relatives. CUP with head and neck region metastases associated with relatives' esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative's cancers in the upper aerodigestive tract (2.14) and lung (1.74). The findings, matching metastatic location in CUP and primary cancer in relatives, could be reconciled if these cases of CUP constitute a phenotypically modified primary lacking tissue identification, resulting from epitope immunoediting. Alternatively, CUP metastases arise in a genetically favored tissue environment (soil) promoting growth of both primary cancers and metastases (seeds).

Wang YZ, Chauhan A, Rau J, et al.
Neuroendocrine tumors (NETs) of unknown primary: is early surgical exploration and aggressive debulking justifiable?
Chin Clin Oncol. 2016; 5(1):4 [PubMed] Related Publications
BACKGROUND: Neuroendocrine tumors (NETs) are rare tumors that often present with vague symptoms. Identification and localization of the primary NET can be challenging and the true incidence remains unclear. These patients have been thought to have a poor prognosis compared to those patients with a known primary. Therefore, traditionally the treatments for patients with unknown primaries have been passive and directed towards symptom control and/or cytoreduction of metastatic disease. We hypothesized that NET of unknown primary are predominantly low-grade and easily located surgically and therefore are amendable to surgical debulking and cytoreduction, which will likely increase survival in these patients.
METHODS: The charts for all 342 surgical patients, seen in our clinic at Ochsner-Kenner between 1/2009 and 9/2012 were retrospectively reviewed to determine which patients had a pre-operative diagnosis of a "NET with unknown primary". Twenty-two patients (6.4%) were identified. For these patients, the rate of successful surgical exploration in which a primary site was identified was recorded. Survival for these "unknown primary" patients were compared to a large similar group of NET patients from a recent study collected from this same Ochsner clinic group.
RESULTS: Twenty-two (22/342, 6.4%) NET patients with a pre-operative diagnosis of an unknown primary were explored and cytoreduced. The primary tumor site was identified in all 22 patients (100%). The primary sites identified for these patients were 19 small intestines (86.4%) and 3 pancreatic (13.6%). All 22 patients had low-grade tumors and all were still alive as of 9/2012, not allowing for a survival curve to be generated.
CONCLUSIONS: Unknown primary NETs are not associated with a poor prognosis as previously reported. Timely surgical exploration and debulking always results in the identification of the primary and a maximum cytoreduction. Early surgical exploration with aggressive debulking is indicated for the treatment of these patients, as for the known counterpart.

McDowell LJ, Young RJ, Johnston ML, et al.
p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary.
Cancer. 2016; 122(8):1201-8 [PubMed] Related Publications
BACKGROUND: The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear.
METHODS: One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes.
RESULTS: The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status.
CONCLUSIONS: p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.

Bankar S, Patkar S, Desai S, Shrikhande SV
Unusual presentation of melanoma of unknown primary origin: A case report and review of literature.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):1025 [PubMed] Related Publications
Malignant melanomas often present with metastasis to regional lymph nodes. Patients are also known to present with metastatic nodes in the absence of a known primary. However metastatic melanoma involving the stomach is rare in the scenario of an unknown primary lesion. We present a case of a 41-year-old lady who was treated for nodal disease in the right axilla 8. months earlier with an unknown primary. She later presented to us with a recurrent right axillary swelling and on evaluation was found to also have a nodular deposit on the greater curvature of the stomach. Histopathology of the deposit in conjunction with immunohistochemical markers S.100P, Melan-A and HMB-45, confirmed the diagnosis of malignant melanoma. The patient underwent surgical excision of both lesions and is now on regular follow-up.

Samadder NJ, Smith KR, Hanson H, et al.
Familial Risk in Patients With Carcinoma of Unknown Primary.
JAMA Oncol. 2016; 2(3):340-6 [PubMed] Related Publications
IMPORTANCE: Carcinoma of unknown primary (CUP) accounts for 3% to 5% of all cancers and is associated with poor prognosis. Familial clustering of different cancer sites with CUP is unknown and may provide information regarding etiology, as well as elevated cancer risks in relatives.
OBJECTIVE: To quantify the risk of cancer by site in first- and second-degree relatives and first cousins of individuals with CUP.
DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study of patients who received a diagnosis of CUP between 1980 and 2010 identified from the Utah Cancer Registry. Population controls with no CUP diagnosis were sex and age matched 10:1 to patients with CUP. Data about relatives were drawn from the Utah Population Database.
MAIN OUTCOMES AND MEASURES: Familial aggregation of cancer risk in relatives of cases compared with controls using Cox regression analysis.
RESULTS: For the 4160 index patients (median [interquartile range] age, 72 [62-81] years; 47.6% male) who had received a diagnosis of CUP, first-degree relatives were at an elevated risk of CUP themselves (hazard ratio [HR], 1.35 [95% CI, 1.07-1.70]), as well as lung (HR, 1.37 [95% CI, 1.22-1.54]), pancreatic (HR, 1.28 [95% CI, 1.06-1.54]), myeloma (HR, 1.28 [95% CI, 1.01-1.62]), and non-Hodgkin lymphoma (HR, 1.16 [95% CI, >1.00-1.35]) cancers compared with controls without CUP. When the analysis was restricted to relatives of cancer-free controls, additional increased risks for colon (HR, 1.19 [95% CI, 1.06-1.33]) and bladder (HR, 1.18 [95% CI, >1.00-1.38]) cancers were observed. Second-degree relatives of patients with CUP were at a slight increased risk of lung (HR, 1.14 [95% CI, 1.03-1.26]), pancreatic (HR, 1.17 [95% CI, 1.01-1.37]), breast (HR, 1.09 [95% CI, 1.02-1.16]), melanoma (HR, 1.09 [95% CI, >1.00-1.19]), and ovarian (HR, 1.19 [95% CI, 1.02-1.39]) cancers.
CONCLUSIONS AND RELEVANCE: Relatives of patients with CUP are at increased risk of CUP and several other malignant neoplasms, including lung, pancreatic, and colon cancer. The present data may suggest sites of origin for CUP and provide cancer risk information for relatives of patients with CUP that can lead to effective intervention. Relatives of patients with CUP should be aware of the elevated risks for lung, pancreatic, and colon cancer and encouraged to modify risk factors and adhere to site-specific population cancer screening.

Sivars L, Tani E, Näsman A, et al.
Human Papillomavirus as a Diagnostic and Prognostic Tool in Cancer of Unknown Primary in the Head and Neck Region.
Anticancer Res. 2016; 36(2):487-93 [PubMed] Related Publications
Human papillomavirus (HPV) is recognized as a risk factor for oropharyngeal squamous cell carcinomas (SCC), especially tonsillar and base of tongue cancer. Furthermore, HPV-positive tonsillar and base of tongue SCC have a significantly better prognosis than their HPV-negative counterparts and head and neck cancer (HNSCC) in general. HPV has recently also been implicated in cancer of unknown primary (CUP) in the head and neck region, where a primary tumour is not found despite extensive workup. Using fine-needle aspiration cytology to determine CUP HPV status in cervical lymph nodes could be of advantage, since it is minimally invasive and it is assumed that an HPV-positive lymph node metastasis likely has an HPV-positive otopharyngeal SCC origin. We review the current knowledge of HPV in HNSCC, with an emphasis on CUP of the head and neck region, its relation to oropharyngeal, tonsillar and base of tongue SCC and implications of HPV status for diagnosis, prognosis and treatment.

Zhang W, Zhuang H, Servaes S
Abnormal FDG and MIBG Activity in the Bones in a Patient With Neuroblastoma Without Detectable Primary Tumor.
Clin Nucl Med. 2016; 41(8):632-3 [PubMed] Related Publications
Neuroblastoma is among the most common extracranial solid tumors in pediatric patients and typically arises anywhere from the neck to pelvis but most commonly in the adrenal glands. It is extremely rare for a patient to have extensive metastases from neuroblastoma without primary tumor being identified. We present a 3-year-old with widespread bone and bone marrow involvement of the disease revealed on both FDG PET/CT and MIBG scan, which was pathologically proven as neuroblastoma. However, extensive imaging did not detect primary tumor anywhere.

Ihaddadene R, Corsi DJ, Lazo-Langner A, et al.
Risk factors predictive of occult cancer detection in patients with unprovoked venous thromboembolism.
Blood. 2016; 127(16):2035-7 [PubMed] Free Access to Full Article Related Publications
Risk factors predictive of occult cancer detection in patients with a first unprovoked symptomatic venous thromboembolism (VTE) are unknown. Cox proportional hazard models and multivariate analyses were performed to assess the effect of specific risk factors on occult cancer detection within 1 year of a diagnosis of unprovoked VTE in patients randomized in the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial. A total of 33 (3.9%; 95% CI, 2.8%-5.4%) out of the 854 included patients received a new diagnosis of cancer at 1-year follow-up. Age ≥ 60 years (hazard ratio [HR], 3.11; 95% CI, 1.41-6.89; ITALIC! P= .005), previous provoked VTE (HR, 3.20; 95% CI, 1.19-8.62; ITALIC! P= .022), and current smoker status (HR, 2.80; 95% CI, 1.24-6.33; ITALIC! P= .014) were associated with occult cancer detection. Age, prior provoked VTE, and smoking status may be important predictors of occult cancer detection in patients with first unprovoked VTE. This trial was registered atwww.clinicaltrials.govas #NCT00773448.

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