Transoral endoscopic ultrasonic surgery (TOUSS) in head & neck unknown primary carcinoma investigation.

Metastatic carcinoma of unknown primary (CUP) to cervical lymph nodes represents less than 5% of all head and neck malignancies. Recent publications support the use of transoral surgery during the diagnosis work-up, and transoral endoscopic ultrasonic surgery represent a recently described alternative technique in transoral surgery. A pilot study to assess the feasibility of trans-oral ultrasonic base of tongue (BOT) mucosectomy and bilateral tonsillectomy approach in CUP diagnosis work-up was conducted. Ten patients were included consecutively. In 2 cases (20%) the primary was found, in one case in the right tonsil, and another one in the left BOT. According to our results, the use of trans-oral ultrasonic surgery to perform the base of tongue mucosectomy and bilateral tonsillectomy in CUP patient's during the diagnosis work-up represents an effective option in patients with good anatomical exposure.

Adherence to the World Cancer Research Fund and the American Institute for Cancer Research lifestyle recommendations for cancer prevention and Cancer of Unknown Primary risk.

BACKGROUND & AIMS: The World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) updated their cancer prevention recommendations in 2018. Adherence to these recommendations has been associated with lower cancer risk and mortality. However, adherence in relation to Cancer of Unknown Primary (CUP) risk has not been studied. This study investigates whether adherence to the WCRF/AICR recommendations is associated with CUP risk. METHODS: Data from the prospective Netherlands Cohort Study on diet and cancer was used to measure adherence to the recommendations in relation to CUP risk. The cohort includes 120 852 participants (aged 55-69 years), who completed a self-administered questionnaire on cancer risk factors at baseline. Adherence was investigated with respect to body fatness, physical activity, plant foods, meat consumption and alcohol. Incident CUP cases were identified through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. A follow-up of 20.3 years, resulted in 856 incident CUP cases and 3911 subcohort members with complete information available for case-cohort analyses. Multivariable adjusted hazard ratios were estimated using proportional hazards models and were adjusted for age at baseline, sex, cigarette smoking (status, frequency, and duration) and total energy intake. RESULTS: Highest adherence appeared to be associated with decreased CUP risk in the age-sex adjusted model (HR: 0.76, 95% CI: 0.62-0.92). After additional adjustment for cigarette smoking (status, frequency, and duration), the association attenuated and was no longer statistically significant. No multiplicative interactions were observed between sex nor smoking status and overall adherence in relation to CUP. CONCLUSION: Within this cohort, highest adherence to the WCRF/AICR recommendations is not statistically significantly associated with decreased CUP risk after multivariable adjustment.

Alcohol consumption, cigarette smoking and cancer of unknown primary risk: Results from the Netherlands Cohort Study.

Cancer of unknown primary (CUP) is a metastasised malignancy with no identifiable primary tumour origin. Despite the frequent occurrence and bleak prognosis of CUP, research into its aetiology is scarce. Our study investigates alcohol consumption, tobacco smoking and CUP risk. We used data from the Netherlands Cohort Study, a cohort that includes 120 852 participants aged 55 to 69 years, who completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 CUP cases and 4288 subcohort members were available for case-cohort analyses. Multivariable-adjusted hazard ratios (HRs) were calculated using proportional hazard models. In general, CUP risk increased with higher levels of alcohol intake (Ptrend = .02). The association was more pronounced in participants who drank ≥30 g of ethanol per day (HR: 1.57, 95% confidence interval [CI]: 1.20-2.05) compared to abstainers. Current smokers were at an increased CUP risk (HR: 1.59, 95% CI: 1.29-1.97) compared to never smokers. We observed that the more the cigarettes or the longer a participant smoked, the higher the CUP risk was (Ptrend = .003 and Ptrend = .02, respectively). Interaction on additive scale was found for participants with the highest exposure categories of alcohol consumption and cigarette smoking frequency and CUP risk. Our findings demonstrate that alcohol consumption and cigarette smoking are associated with increased CUP risk. Lifestyle recommendations for cancer prevention regarding not drinking alcohol and avoiding exposure to smoking are therefore also valid for CUP.

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

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. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.

Comparative genetic profiling aids diagnosis and clinical decision making in challenging cases of CUP syndrome.

Cancer of unknown primary (CUP) denotes cancer cases where metastatic spread is histologically confirmed, but no respective primary tumor can be identified. The challenging diagnosis of CUP is further complicated in cases with previously identified malignancies or with dubious clonal relationship between metastatic sites due to ambiguous histology. Our study aims at elucidating clonal relationships by comparing the respective mutational spectra. Targeted next-generation sequencing (NGS) employing formalin-fixed and paraffin-embedded (FFPE) tumor tissue was performed on 174 consecutive CUP patients. Among these, 43/174 (24.7%) patients had a documented prior malignancy. Data on pairwise targeted NGS testing to address clonal relationships between the previous malignancy and the presumed CUP (n = 11) or between different CUP metastatic sites (n = 7) was available in 18 patients. NGS could clarify clonal relationships in 16/18 cases. Among the 11 CUP patients with antecedent malignancies, four cases were clonally independent of the previous malignancy but harbored deleterious germline mutations in BRCA/BAP1/ATM genes. Seven CUP cases were clonally related to the antecedent malignancy, changing the CUP diagnosis to relapse of the prior malignancy. In the seven CUP cases, with doubtfully related metastatic sites, NGS confirmed clonal relationship in five cases and was inconclusive in two. In conclusion, NGS proved an efficient tool to elucidate clonal relationships in clinically challenging CUP cases. Our study cautions against a premature diagnosis of CUP. Relapses of antecedent malignancies should be carefully considered. CUPs clonally independent from the antecedent malignancy should raise a red flag of a potential cancer-predisposing germline mutation.

A clinical practice-based evaluation of the RIETE score in predicting occult cancer in patients with venous thromboembolism.

The association between venous thromboembolism (VTE) and occult cancer is well established. However, the benefit of cancer screening in all VTE patients remains controversial. The Registro Informatizado Enfermedad TromboEmbólica (RIETE) score is a recently proposed risk score to identify VTE patients at high risk of occult cancer. We evaluated the performance of the RIETE score in a routine clinical setting comprising patients presenting with VTE between January 1 and December 31, 2014, at Danderyd University hospital. Out of 488 VTE patients, 47 (9.6%) patients received a new cancer diagnosis during a 24-month follow-up. After exclusion of patients with cancer diagnosed at baseline (≤ 10 days after VTE, n = 16), 472 patients were considered eligible for cancer screening. Among these 472 patients, 31 (6.6%) received a cancer diagnosis during follow-up. The cumulative incidence was high after both unprovoked (8.5%) and provoked (4.8%) VTE. The RIETE score was evaluated in 467 of these patients. Interestingly, a high RIETE score was not significantly associated with cancer diagnosis during follow-up (OR 1.78; 95% CI 0.85-3.63), which was mainly due to a poor performance in women (OR 1.04; 95% CI 0.30-2.83). In summary, we observed a relatively high incidence of occult cancer in both unprovoked and provoked VTE. The RIETE score performed poorly in identifying patients at high risk of occult cancer in our VTE population. Additional risk assessment models are warranted to identify VTE patients who would benefit from extensive cancer screening.

Adult Onset Henoch-Schonlein Purpura associated with a Metastatic Malignancy of Unknown Primary Origin.

The cause of Henoch-Schonlein purpura, or IgA vasculitis, is largely unknown. It has been associated with infections, other rheumatologic triggers, and adverse drug reactions. Rarely, adult Henoch-Schonlein purpura is also associated with solid-tumor malignancies. We present the case of a 66 year-old woman who presented with Henoch-Schonlein purpura associated with a metastatic malignancy of unknown primary origin. We recommend that adult patients presenting with Henoch-Schonlein purpura, especially those with no identifiable trigger, receive age-appropriate work-up for potential malignancy.

Cancer of unknown primary-Epidemiological trends and relevance of comprehensive genomic profiling.

BACKGROUND: Cancer of unknown primary (CUP) is a distinct clinicopathological entity with poor prognosis, frequently resistant to chemotherapy. Comprehensive genomic profiling (CGP) by next-generation sequencing potentially identifies novel treatment options for CUP patients. The objective of this study was to determine incidence and survival trends and to discuss the value of CGP in CUP patients. METHODS: Age-standardized incidence rates (ASR) per 100 000 were calculated for 2935 CUP patients from 1981 to 2014 using cancer registry data of the canton of Zurich, Switzerland. Kaplan-Meier survival curves were estimated for sex, age, and histological groups. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR). A literature review was conducted to assess the current use of CGP in CUP patients. RESULTS: ASR of CUP increased from 10.3 to 17.6 between 1981 and 1997 and decreased to 5.8/100 000 in 2014. Mean overall survival remained stable. Mortality was significantly lower for patients with squamous cell carcinoma (HR 0.48 [95% CI, 0.41-0.57]) and neuroendocrine carcinoma (0.75 [0.63-0.88]) and higher for unclassified neoplasms (1.25 [1.13-1.66]) compared to adenocarcinomas. The literature review identified 10 studies using CGP of CUP tissue. Clinically relevant mutations were identified in up to 85% of CUP patients, of which 13%-64% may benefit from currently available drugs. CONCLUSIONS: CUP incidence decreased probably due to improved diagnostics, but mortality did not improve over the last 34 years. CGP testing may help to identify molecular signatures in CUP patients and enable targeted treatment.

Occult breast cancer may originate from ectopic breast tissue present in axillary lymph nodes.

PURPOSE: Occult breast cancer (OBC) is classified as a carcinoma of unknown primary, and involves axillary lymphadenopathy and is histologically consistent with metastatic breast cancer. OBC has been conventionally considered as a metastatic lymph node lesion, the origin of which is an undetectable breast tumor. Therefore, OBC patients would usually have undergone axillary lymph node dissection, and mastectomy or whole breast radiotherapy (WBRT). However, majority of OBC reports have been based on cases that were diagnosed during a period when diagnostics was still relatively primitive, and when magnetic resonance imaging was not yet a standard preoperative assessment. Therefore, there have been many false negatives in the breast based on preoperative assessment. METHODS: We herein hypothesize that the origin of OBC is ectopic breast tissue present in axillary lymph nodes (ALNs). If our hypothesis is true, mastectomy and WBRT may be unnecessary for OBC patients. RESULTS: Our hypothesis is supported by several findings. First, advances in radiological imaging have suggested that a primary breast tumor is absent in OBC patients. Second, proliferative breast lesions arising from ectopic breast present in ALNs have been reported. Lastly, cellular subtypes in OBC based on immunohistochemistry are of various types including ordinary breast cancer and the prognosis is not worse than stage II breast cancer. CONCLUSION: It is important to distinguish between "primary" OBC in ALNs and "metastatic" OBC from micro-primary breast tumor. Further studies are required to determine if omission of mastectomy and WBRT is acceptable.

Malignancy dominated with rheumatic manifestations: A retrospective single-center analysis.

Paraneoplastic rheumatic syndromes comprise a heterogeneous group of disorders characterized by typical rheumatic manifestations but without direct invasion by the tumor or metastases. The clinical features and malignancy-associated risk factors of 21 patients with paraneoplastic rheumatic syndromes, including 11 men and 10 women with a mean age of 56.3 ± 13.1 years, were characterized by a retrospective review. All patients were diagnosed with malignancy within 2 years of rheumatism diagnosis. Patients suffering from solid malignancies accounted for the majority (62%); hematological malignancies were observed in the remainder. Arthritis (48%), lymph node enlargement (38%), skin rash (38%), weight loss (29%), fever/chills (24%), fatigue (24%), muscle soreness (24%) and smoking history (29%) were common findings. Except for 8 patients (38%) who tested positive for anti-nuclear antibody (ANA) and 9 positive for rheumatoid factor (RF), all patients tested negative for anti-extractable nuclear antigen (ENA) antibodies. Rheumatic disorders with a typical clinical presentation in older patients and nonspecific systemic features should alert clinicians to search for an occult malignancy. Patients with rheumatic disease must be closely followed to screen for malignancies, particularly within 2 years of rheumatism diagnosis.

Diagnosis and Treatment of Testicular Cancer: A Clinician's Perspective.

Testicular germ cell tumors (GCTs) include seminoma and nonseminoma. Chance of cure is excellent for clinical stage I disease regardless of whether adjuvant treatment or a surveillance strategy with treatment only for those who relapse is used. Risk of recurrence is greater in nonseminoma with evidence of lymphovascular invasion, but most can be salvaged with chemotherapy and survival rates remain high. This article outlines key pathologic and clinical considerations in clinical stage I seminoma, nonseminoma, advanced disease, and assessment of cancer of unknown primary as a potential GCT.

Risk factors for cancers of unknown primary site: Results from the prospective EPIC cohort.

Cancer of unknown primary site (CUP) may be called an "orphan" disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N=476,940). During prospective follow-up, a total of 651 cases of incident cases of CUP were detected (ICD-O-2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24-5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09-8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking-related tumors, in particular.

Screening for occult malignancy with FDG-PET/CT in patients with unprovoked venous thromboembolism.

Extensive screening strategies to detect occult cancer in patients with unprovoked venous thromboembolism (VTE) are complex and no benefit in terms of survival has been reported. FDG-PET/CT (2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography), a noninvasive technique for the diagnosis and staging of malignancies, could be useful in this setting. Consecutive patients ≥ 50 years with a first unprovoked VTE episode were prospectively included. Screening with FDG-PET/CT was performed 3-4 weeks after the index event. If positive, appropriate diagnostic work-up was programmed. Clinical follow-up continued for 2 years. Blood samples were collected to assess coagulation biomarkers. FDG-PET/CT was negative in 68/99 patients (68.7%), while suspicious FDG uptake was detected in 31/99 patients (31.3%). Additional diagnostic work-up confirmed a malignancy in 7/31 patients (22.6%), with six of them at early stage. During follow-up, two patients with negative FDG-PET/CT were diagnosed with cancer. Sensitivity (S), positive (PPV) and negative predictive values (NPV) of FDG-PET/CT as single tool for the detection of occult malignancy were 77.8% (95% CI: 0.51-1), 22.6% (95% CI: 0.08-0.37) and 97.1% (95% CI: 0.93-1), respectively. Median tissue factor (TF) activity in patients with occult cancer was 5.38 pM vs. 2.40 pM in those without cancer (p = 0.03). Limitation of FDG-PET/CT screening to patients with TF activity > 2.8 pM would improve the PPV to 37.5% and reduce the costs of a single cancer diagnosis from 20,711€ to 11,670€. FDG-PET/CT is feasible for the screening of occult cancer in patients with unprovoked VTE, showing high S and NPV. The addition of TF activity determination may be useful for patient selection.

[Papilledema of unknown cause]. / Unklare Papillenschwellung.

Orbital metastases occur in 2-5 % of cancer patients. Common primary sites that cause orbital metastases are breast, lung and prostate cancer. In up to 25 % of patients orbital metastasis is the initial sign of an unknown primary tumor. Clinical symptoms are proptosis, ocular motility disorder and visual impairment. Imaging procedures may be useful in diagnosing orbital metastases but are not specific. Treatment is palliative. Radiotherapy, chemotherapy and surgical debulkment in selected patients are treatment options.

Carcinoma of unknown primary (CUP); some considerations about pathogenesis and diagnostic strategy, particularly focusing on CUPS pertaining to the Urology.

The term "carcinoma of unknown primary" (CUP) defines a malignant condition in which a metastatic cancer is documented in absence of a detectable primary site. It occurs in about 2÷6 % of cancer patients, according to various literature reports. The primary tumor site results indefinable because of several either single or associated factors, even remaining occult at autopsy in 15÷25% of CUP patients. The metastatic spread pattern of CUP is quite unlike that expected for analogous known primary malignancy. For instance, the unknown prostate cancer often metastasizes to the lungs and liver while the its known analogous usually spreads to the bone. Whether certain genetic abnormalities might play a role in determining a CUP condition, it remains undefined. Most CUP are adenocarcinoma, squamous cell carcinoma, either undifferentiated or differentiated carcinoma, whereas less frequently may be sarcoma, melanoma or neuroendocrine tumor. As CUP diagnostic management is concerned, two opposite approach modalities may be adopted, one, named "shotgun modality", consisting in a multiplicity of examinations aimed at achieving the identification of the primary tumor and the other, a nihilistic modality, by adopting tout court a palliative therapy of the metastatic disease. A reasonable intermediate diagnostic strategy consists in undertaking some procedures with a specific target and low cost/benefit ratio. Selected imaging studies, serum tumor markers, immunohistochemical analyses and genetic- molecular examinations on biopsy material allow sometimes to reach the detection of primary malignancies that might be responsive to a potential treatments. Nevertheless, in spite of recent sophisticated -laboratory and imaging progress, CUP remains a strong challenge in clinical oncology.

Polyarthritis as a prewarning sign of occult lung cancer.

Cancer polyarthritis is an uncommon, paraneoplastic manifestation of some solid and hematological malignancies. Herein, we report the case of a 55-year-old woman who recently experienced polyarthritis for 2 months. On admission, the patient developed cough, expectoration, and fever. According to the clinical manifestations and the findings in radiological examinations and sputum cultures, pneumonia was considered. No evidence of lung cancer was noted by repeated computed tomography scan of lung, single bronchoscopy, or computed tomography-guided lung biopsy. Ultimately, the second bronchoscopy with biopsy was carried out, and lung adenocarcinoma was confirmed by pathological examination. Symptoms of polyarthritis starting 2 months before the symptoms of her lung cancer in the present case leads us to believe that polyarthritis may be a manifestation of paraneoplastic syndrome. Arthritis resolved after anticancer therapy. Our report indicates that polyarthritis of unknown cause may be suspected as a manifestation of malignancies.