Unknown Primary Tumor Research Articles

Eight-and-a-Half Syndrome as The First Presentation of Unknown Metastatic Primary Tumor

Eight-and-a-Half Syndrome as The First Presentation of Unknown Metastatic Primary Tumor

SURG-10. The evolving role of neurosurgery for central nervous system metastases in the era of personalized medicine

BackgroundNovel therapies translating into improved survival of patients with advanced cancer have emerged. The number of metastases in the central nervous system is therefore seen to increase. Neurosurgery assumes an expanding role within multi-disciplinary care structures for such patients.MethodsWe performed a comprehensive literature review on the current status of neurosurgery for brain metastases patients. Based on the extracted data, we developed a review from experts in the field on the role of brain metastasis surgery in the era of personalized medicine.ResultsTraditionally, three metastases were considered the cutoff to offer surgical resection. With respect to the clinical status, the resection of a symptomatic mass may nowadays be considered even in presence of multiple tumors in a multimodal setting: surgical resection of brain metastasis provides immediate relief from mass effect-related symptoms and histology in case of unknown primary tumor; surgery may help stabilizing the disease, thus enabling further therapy; and in situations where immunotherapy is considered and non-surgical management would require long-term steroid administration, surgery may also provide expeditious relief of edema and reduction of needs for steroids. In patients with multiple brain metastasis and mixed response to non-surgical therapy, tumor resampling may allow tissue analysis for expression of molecular tumor targets. In patients with leptomeningeal dissemination and consecutive hydrocephalus, ventriculo-peritoneal shunting improves quality of life but also allows for time to administer more therapy thus prolonging survival. Addressing the limited efficacy of many oncological drugs for brain metastases, clinical trial protocols in which surgical specimens are analyzed for pre-surgically administered agents may offer pharmacodynamic insights.ConclusionComprehensive neurosurgical care will have to be an integral element of multi-disciplinary oncological centres providing care to patients with brain metastases to improve on therapy and tumour biology research.

Does knowledge of the primary tumour affect survival after surgery for spinal metastatic disease? A retrospective longitudinal cohort study

ObjectivesTo compare survival after surgery for patients with spinal metastatic disease with known primary tumour (KPT) versus patients with unknown primary tumour (UPT).Participants393 patients 18 years or older (270 men...

Immunohistochemically detectable thyroglobulin expression in extrathyroidal cancer is 100% specific for thyroidal tumor origin

Thyroglobulin is a secreted 660 kDa glycoprotein produced by thyroid follicular cells used in diagnostic pathology to secure or exclude a thyroidal origin of metastases of unknown primary tumors. This study was performed to estimate specificity of thyroglobulin immunohistochemistry. 9974 tumor samples from 109 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Thyroglobulin was strongly expressed in all normal thyroid samples but not in any other normal tissues. Thyroglobulin immunostaining was detected in 99.1% of 106 thyroid adenomas, 98.1% of 364 papillary, 95.2% of 147 follicular, and 7.5% of 40 anaplastic thyroid cancers. Twelve of 15 thyroid samples that were thyroglobulin negative on TMAs showed at least a weak focal thyroglobulin positivity in corresponding large sections, suggesting higher sensitivity of large section analysis. Thyroglobulin positivity in one diffuse large B-cell lymphoma of the thyroid, one chondrosarcoma metastasis to the thyroid, and 42.4% of 92 medullary thyroid cancers was considered to be caused by diffusion of thyroidal colloid from destroyed or even intact adjacent follicles. Thyroglobulin positivity was, however, not seen in 6403 extrathyroidal tumors from 104 different tumor types and subtypes. Our data demonstrate a complete specificity of positive thyroglobulin immunostaining for thyroid origin in tumor tissues obtained from extrathyroidal locations. However, for all tumors located within the thyroid, false positivity can occur as a result of tissue contamination by thyroglobulin rich thyroid colloid from adjacent normal tissue.

Safety and Efficacy of Crizotinib in ALK-Positive Lymphomas: A Phase 1b Open-Label Study

IntroductionCrizotinib, an inhibitor of ALK, MET and ROS1, is approved for patients with ALK-positive or ROS1-positive advanced non-small-cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMT).MethodsIn this open-label, ongoing, multicenter, single-arm phase 1b study (PROFILE 1013 [NCT01121588]), male or female patients, aged ≥15 years, with ECOG performance status 0−3,with ALK-positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg BID. Primary endpoints were safety and objective responses, based on RECIST v1.1 or NCI International Response Criteria.ResultsForty-four patients were enrolled (lymphoma=18, IMT=9, other tumors=17). In the lymphoma group, 17/18 of patients were evaluable for response. Objective response rate was 52.9% (95% CI 27.8-77.0) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 66.7% (95% CI 29.9-92.5) for IMT, with 1 CR and 5 PRs; and 11.8% (95% CI 1.5-36.4) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively.Median treatment duration was close to 3 years for lymphoma patients (150.7 weeks [range 0.1-249.3]) and IMT patients (142.9 weeks [range 21.1-160.0]) and was 1 month for patients with other tumors. Treatment with any other anti-cancer treatment was not allowed.In lymphoma patients, median PFS has not been reached due to a small number of events (33.3%) (Figure 1). The estimated probability of lymphoma patients being progression free at 2 years was 63.0% (95% CI: 35.3, 81.4). Median OS was also not reached as OS data were immature, with 72.2% of patients with lymphoma still alive at the cutoff (Figure 2). Only 1 patient received bone marrow transplant during crizotinib treatment and was censored for anti-tumor activity.In IMT patients, median PFS was also not reached due to a small number of events (33.3%)(Figure 1). The estimated probability of IMT patients being progression free at 2 years was 66.7% (95% CI: 28.2, 87.8). In addition, median OS was not reached as 66.7% of patients with IMT were alive at data cutoff (Figure 2).In the other tumors group median PFS was 1.3 months (95% CI: 1.1, 3.9) (Figure 1) with a high number of events (88.2%), PFS at 2 years was 6.3% (95% CI: 0.4, 24.7) and median OS was 8.3 months (95% CI: 2.2, 16.9) (Figure 2).Treatment-related adverse events (TRAEs) occurred in a total of 39 (88.6%) patients. Mild to moderate diarrhea and vision disorder were the most common TRAEs reported (45.5%), most of which were grade 1. Overall, 9 patients (20.5%) experienced a serious adverse event (SAE) considered to be related to crizotinib treatment. The most common SAE considered as possibly treatment-related was grade 4 blood creatine phosphokinase increase reported in 3 patients (6.8%), all in clinical response and concurrent with strenuous physical activity. Grade 5 AEs considered by the investigator as treatment-related occurred in 2 patients: cerebral infarction in a patient with unknown primary tumor and multiple brain metastasis, concurrent with disease progression, and interstitial lung disease in a patient with nasopharyngeal carcinoma. Subsequent review by an independent radiology committee, consisting of a pulmonologist, radiologist and oncologist, indicated that this event was aspiration pneumonia, non-drug-related.ConclusionsThese findings indicate a strong and durable activity of crizotinib in ALK-positive lymphomas and IMTs. Treatment duration was much longer than usual treatment in NSCLC patients and the safety profile was consistent with the known safety profile of crizotinib, even with long-term treatment. [Display omitted] DisclosuresGambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Braiteh:Merck: Honoraria, Other: Travels, Speakers Bureau; Lexicon: Honoraria; Insys: Honoraria, Other: Travels, Speakers Bureau; Ipsen: Honoraria, Other: Travels, Speakers Bureau; Incyte: Honoraria, Other: Travels, Speakers Bureau; Heron Therapeutics: Honoraria, Other: Travels; Halozyme Therapeutics: Other: Travels; Eli Lilly: Honoraria, Other: Travels, Speakers Bureau; Clovis: Honoraria, Speakers Bureau; Celgene: Other: Travels, Speakers Bureau; Bristol Myers Squibb: Other: Travels, Speakers Bureau; Boehringer Ingelheim: Honoraria, Other: Travels, Speakers Bureau; Biotheranostics: Honoraria, Speakers Bureau; Bayer: Honoraria, Other: Travels; Astra Zeneca/Medimmune: Honoraria, Other: Travels, Speakers Bureau; Amgen: Honoraria, Other: Travels, Speakers Bureau; Merrimack: Honoraria, Other: Travels, Speakers Bureau; Pfizer: Honoraria, Other: Travels, Speakers Bureau; Roche/Genentech: Honoraria, Other: Travels, Speakers Bureau. Ahn:Boehringer Ingelheim: Honoraria; Menarini: Honoraria; Roche: Honoraria; Janssen: Honoraria; Eisai: Honoraria; BMS: Honoraria. Taylor:Eisai Inc.: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Trillium Therapeutics: Consultancy, Honoraria; Blue Print Medicines: Consultancy, Honoraria. Van Tine:Pfizer: Research Funding; Novartis: Consultancy, Speakers Bureau; Merch: Research Funding; Lilly: Consultancy, Speakers Bureau; J&J: Consultancy, Speakers Bureau; Caris: Consultancy, Speakers Bureau. Wu:Celgene International Sàrl: Research Funding. Paolini:Pfizer: Employment, Equity Ownership. Li:Pfizer: Employment.

Metastatic Liver Tumors in Surgical Pathology: Impact of Contemporary Diagnostic and Therapeutic Paradigms in a Tertiary Care Center.

We analyzed metastatic liver tumors received in the department of pathology in a tertiary care center over a 3-year period. There were 509 metastatic liver tumors; counterintuitively, there were as many resections (235 cases) as biopsies (274 cases). This unexpected finding reflects contemporaneous organ-specific paradigms for diagnosis and management of metastatic liver disease in oncologic practice, and the association of our practice with a National Cancer Institute-designated comprehensive cancer center with expertise and specialization in liver surgery. We receive a large number of resections for metastatic liver tumors because metastasectomy from a variety of primary tumors is associated with improved overall, and in many instances, disease-free, long-term survival. Metastatic colorectal carcinomas, metastatic neuroendocrine tumors, and metastatic gastrointestinal stromal tumors constituted 78% of resections because the largest body of literature and cumulative experience exists for these lesions. In contrast, breast carcinomas and pancreatic carcinomas, which are the next common metastatic liver tumors were biopsied but rarely resected, because metastasectomy is not the standard of care for these tumors. Immunohistochemistry was performed in less than a quarter of the total number of cases (23%), because the primary tumor site was known in the vast majority of cases. Of the 42 cases with unknown primary tumor, it was elucidated in 50% of the cases by immunohistochemical and clinical work-up. Of the cases with known primary tumor, immunohistochemistry was performed mostly in metastatic breast, colon, and lung carcinomas. In these cases, biomarker analyses provided additional information relevant to clinical management.

Confirmatory germline testing for presumed germline pathogenic variants using tumor-only testing.

e22524 Background: Presumed germline pathogenic variants (PGPVs) can be detected in tumor tissues using comprehensive genomic profiling. Clinicians and patients can decide whether to conduct confirmatory germline testing or not. However, the promoting and obstructive factors for confirmatory germline testing are unclear. Methods: This single institutional retrospective study aimed to identify factors related to confirmatory germline testing in patients with PGPVs. Between April 2015 and April 2019, 270 consecutive patients with cancers of unknown primary site, rare tumors, or solid tumors refractory to standard chemotherapy, who underwent tumor-only comprehensive genomic profiling were reviewed. PGPVs were proposed to be disclosed as variants to the patients by our institutional molecular tumor board. Univariate logistic regression analysis was conducted to investigate the relationship between each patient’s characteristics and confirmatory germline testing. Factors showing a statistical relationship (p < 0.10 in univariate analyses) were included in multivariate logistic regression analysis with a backward selection of variables. Statistical significance was set at p < 0.05. Results: Of the 270 patients who underwent tumor-only comprehensive genomic profiling, 77 possessed PGPVs. The most common PGPVs were TP53 (n = 56), APC (n = 9), PTEN (n = 7), RB1 (n = 6), and BRCA2 (n = 6). Among the 77 patients, only 11 (14.3%) chose to undergo confirmatory germline testing. Multivariate logistic regression analysis revealed that the person disclosing the results (experienced oncologists with knowledge of cancer genome medicine vs. others, odds ratio [OR]: 27.7, 95% confidence interval [CI]: 4.60–167) and study period (OR: 0.110, 95% CI: 0.015–0.787) were independently and significantly associated with confirmatory germline testing. Conclusions: These findings indicate that fostering genomic competency in oncologists and collaborating with genetic experts would facilitate cancer patients and their families to receive genetic medical services in the process of cancer genomic profiling.

Large neck metastasis with unknown primary tumor: A case report

Introduction. Metastatic head and neck carcinoma (HNC) from an unknown primary tumor is defined as a metastatic disease in the neck?s lymph nodes without evidence of a primary tumor after appropriate investigation. Multiple national guidelines recommend taking essential steps in diagnostic protocols which involve a detailed clinical exam with radiological imaging, fine-needle aspiration (FNA) biopsy of the cervical tumor, esophagogastroduodenoscopy (EGD) with palatine and lingual tonsillectomy, immunohistochemical staining, and human papillomavirus (HPV) detection. Treatment of HNCs of unknown primary origin involves surgery (neck dissection) with radiotherapy (RT), while some authors recommend chemo-radiotherapy in cases of advanced regional disease. Case report. A 44-year-old male was referred to the tertiary medical center because of a large ulcero-infiltrative cervical mass on the right side. Examination of the head and neck and flexible nasopharyngolaryngeal endoscopy was conducted, followed by computed tomography (CT) of the head, neck, and thorax with intravenous contrast. The primary localization of the tumor was not confirmed by these diagnostic methods. An open biopsy of the neck mass established a histopathology diagnosis of metastatic squamous cell carcinoma (SCC). Results of EGD with biopsies and bilateral tonsillectomy were negative for malignancy. Treatment included extended radical neck dissection with reconstruction and postoperative ipsilateral RT. The patient presented with an extensive pharyngolaryngeal tumor five years after the first surgery. Biopsy with histopathology examination confirmed the diagnosis of SCC. Conclusion. A structured step-by-step diagnostic approach to identifying the primary site of the metastatic HNC is mandatory. Substantial advances in diagnostics and operative techniques have increased the likelihood of primary tumor identification and detection of the disease's regional and systemic spread. The purpose of adherence to guidelines results in higher overall survival and longer regional disease-free survival in these patients.

Merkel cell carcinoma: A systematic review of the demographic and clinical characteristics of 847 cases in Japan.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin associated with Merkel cell polyomavirus and immunosuppression. Although MCC incidence is rising worldwide, MCC has not been sufficiently investigated in Japan. This study aimed to determine MCC demographics in Japan, including incidence, age, sex, location, spontaneous regression, and pure/combined MCC. Using PubMed and Igaku Chuo Zasshi, 847 MCC cases between 1985 and 2015 were extracted, and the main epidemiological characteristics were described. The mean age of all patients was 77.5years. Regarding the characterized lesions, 63.0% were located on the head and neck, 5.2% on the trunk, 12.6% on the upper limb, 15.1% on the lower limb, 3.5% on the buttocks, and 0.6% on the genitals. Histopathological information regarding the presence of other malignancies could be retrieved in 611 cases, and a coexisting malignancy, mainly squamous cell carcinoma and Bowen's disease, was present in 14.2%. Subcutaneous MCC was observed in 31 patients with a male:female ratio of 1.07 (16 men/15 women). Nodal lesions with unknown primary tumor location were described in 19 patients with a male:female ratio of 0.9 (nine men/10 women) and a mean age of 77.7years. Of 640 evaluable cases, spontaneous regression developed in 9.1%. Among those 58 patients, the male:female ratio was 1:2.1 in 56 evaluable cases (18 men/38 women). Merkel cell polyomavirus was assessed in 180 patients, and the virus was detected in 31.1% and not detected in 68.9% of the patients. MCC is a rare disease in Japan, with incidence rates and male:female ratios differing from those in the USA and European countries. Besides, this study reveals the high frequency of subcutaneous MCC and MCC with divergent differentiation patterns and spontaneous regression in Japan compared to other countries.

National trends in clinical and pathologic staging for upper tract urothelial carcinoma: Implications for neoadjuvant chemotherapy

IntroductionWith growing support of perioperative chemotherapy for upper tract urothelial carcinoma (UTUC), current biopsy methods are challenging, and little is known as to the degree to which patients would appropriately receive neoadjuvant chemotherapy (NAC) from biopsy alone. Herein, we sought to assess the rates of appropriate clinical use of NAC and identify clinicopathologic factors associated with aggressive UTUC amongst patients undergoing radical nephroureterectomy (RNU) for clinically localized disease. MethodsFrom 2004 to 2013, we identified all treatment naïve patients diagnosed with clinically localized, high grade UTUC (cTa-4Nx) who underwent RNU from the National Cancer Database (NCDB). Pathologic criteria for NAC (pT2-4N0,x; pTanyN1) from RNU represented the primary outcome. Bivariate and multivariable analyses were utilized to identify covariates associated with primary outcome to determine appropriate use of NAC. ResultsDuring the study interval, 5,362 patients were diagnosed with clinically localized UTUC and underwent RNU. Overall, 49.1% of patients presented with an unknown primary tumor stage (Tx) and 24.5% had invasive UTUC from biopsy. On multivariable analysis, upper tract tumor size was associated with invasive UTUC eligible for NAC (all P < 0.05). Amongst patients with cTx UTUC from biopsy, half of patients had pathologic noninvasive UTUC (pTa,is,1) from RNU and would be overtreated with NAC. ConclusionSignificant uncertainty persists in assigning primary upper tract tumor depth and represents a key barrier to widespread implementation of NAC for patients with high grade UTUC. Further research is needed to more accurately determine clinical criteria to identify patients for NAC.

Merkel Cell Carcinoma of Unknown Primary: Immunohistochemical and Molecular Analyses Reveal Distinct UV-Signature/MCPyV-Negative and High Immunogenicity/MCPyV-Positive Profiles.

Simple SummaryMerkel cell carcinomas (MCCs) of unknown primary are defined as deep-seated tumors without an associated cutaneous tumor. Although the distinction has important clinical implications, it remains unclear whether these tumors represent primary tumors of lymph nodes or metastatic cutaneous primaries. We compared the immunohistochemical profiles of four groups of Merkel cell carcinomas (virus-positive and virus-negative unknown primary tumors and virus-positive and virus-negative cutaneous tumors) and performed molecular studies on the unknown primary tumors. Virus-positive and virus-negative Merkel cell carcinomas of unknown primary (MCC-UPs) exhibited an immunoprofile similar to virus-positive and virus-negative primary cutaneous MCCs, respectively. Similar to primary cutaneous Merkel cell carcinomas, virus-negative unknown primary tumors exhibited UV signatures and frequent high tumor mutational burdens, whereas few molecular alterations were noted in virus-positive tumors. Although additional studies are warranted for the virus-positive cases, our findings are supportive of a cutaneous metastatic origin for virus-negative Merkel cell carcinomas of unknown primary.Background: Merkel cell carcinomas of unknown primary (MCC-UPs) are defined as deep-seated tumors without an associated cutaneous tumor. Although the distinction has important clinical implications, it remains unclear whether these tumors represent primary tumors of lymph nodes or metastatic cutaneous primaries. Methods: We compared the immunohistochemical profiles of four groups of MCCs (Merkel cell polyomavirus (MCPyV)-positive UP, MCPyV-negative UP, MCPyV-positive known primary (KP), and MCPyV-negative KP) using B-cell and pre-B-cell markers, cell cycle regulating proteins, follicular stem cell markers, and immune markers, and performed next generation and Sanger sequencing. Results: Virus-positive and virus-negative MCC-UPs exhibited an immunoprofile similar to virus-positive and virus-negative primary cutaneous MCCs, respectively. MCC-UP tumors (both virus-positive and -negative) were immunogenic with similar or even higher tumoral PD-L1 expression and intratumoral CD8 and FoxP3 infiltrates in comparison to MCPyV-positive cutaneous tumors. In addition, similar to primary cutaneous MCCs, MCPyV-negative MCC-UPs exhibited UV signatures and frequent high tumor mutational burdens, whereas few molecular alterations were noted in MCPyV-positive MCC-UPs. Conclusions: Our results showed distinct UV-signatures in MCPyV-negative tumors and high immunogenicity in MCPyV-positive tumors. Although additional studies are warranted for the MCPyV-positive cases, our findings are supportive of a cutaneous metastatic origin for MCPyV-negative MCC-UP tumors.

UNKNOWN PRIMARY TUMOR SITES IN SPINAL METASTASIS

ABSTRACT Objective: The goal of the study was to report the prevalence of spinal metastasis with unknown primary tumor, clinical features, treatment results and patient survival. Methods: A retrospective evaluation of 103 patients with spinal metastasis and epidural compression, who underwent surgical treatment between March 2009 and August 2015. The prevalence of metastatic spinal tumor with unknown primary tumor was evaluated, as well clinical features, survival and treatment results. Results: Of 103 patients with spinal metastasis and epidural compression, seven patients (6.8%) with unknown primary tumor site were identified; five (71.4%) male and two (28.6%) female, with ages ranging from 37 to 67 years (50.7 years). The metastasis was located in the thoracic spine in six of the patients (85.7%) and in the cervical spine in one (14.3%). The mean survival time was 44.8 days. Conclusion: Spinal metastasis with unknown primary tumor was found in 6.8% of patients. The prognosis and outcomes were poor, and patients had poor survival rates. Level of evidence III; Experimental study.

Metastasis to the thyroid gland: Characterization and survival of an institutional series spanning 28 years

IntroductionSecondary neoplasms in the thyroid are rare. The study aim was to provide an overview of non-thyroid tumours that metastasize to the thyroid through our institutional experience. Materials and methodsThis study entailed a review of the pathology database searching for patients with metastasis to the thyroid at the Karolinska University Hospital between 1992 and 2019 and review of their medical files. ResultsOut of 1939 surgical procedures with a histopathological diagnosis of a thyroid malignancy, 31 cases (1.6%, 65% females) with a diagnosis of metastatic epithelial neoplasms to the thyroid gland were identified. The median age at discovery of the thyroid metastasis was 68 years (range 48–85). The most common primary tumours were clear cell renal cell carcinoma (ccRCC) (36%), followed by non-small cell lung cancer (19%), oesophageal cancer (16%), head and neck malignancies (16%), malignant melanoma (10%) and unknown primary tumour (3%). The median time from the diagnosis of the primary tumour to diagnosis of the thyroid metastasis was 20 months (0–232) and was longest for patients with ccRCC (median 107 months). At 12 months after the non-thyroid metastasis diagnosis 48% had died. The longest survival was observed in ccRCC and the shortest in lung cancer. Surgical management of the metastasis was associated with improved survival (25 vs 3.8 months, p = 0.001). ConclusionsNon-thyroid metastases to the thyroid were rare but should be suspected in patients with previous history of non-thyroid malignancy and a thyroid nodule. Prognosis was poor, but surgical management was beneficial in selected patients.

Evaluation of the Patients with spinal metastasis of unknown primary tumor origin.

Background: The spine is not only the most frequent site of skeletal metastasis of a known carcinoma but it is also the most frequent site of bone metastasis of unknown primary tumor origin, however, most of the existing reports that analyzed the clinical features of patients who presented with skeletal metastasis of unknown origin have included cases of bone metastasis at any location. Objective: This study was conducted to analyze the clinical features, survival, and specific diagnostic implications in patients presented with spinal metastasis of unknown primary malignant tumor. Method: In this prospective study, 40 patients presented with spinal metastasis of unknown primary tumor origin to Mosul Oncology Hospital were followed up. Result: The primary malignant tumor was identified in (97.5%) of cases, lung cancer was the most frequently identified primary tumor (35%) followed by carcinoma of the breast (30%) and prostatic cancer (12.5%). We found that Computed tomography scan of the chest, abdomen, and pelvis were the most useful diagnostic modality to identify the primary malignant tumor and there was a significant difference in the overall survival of patients with different primary tumor sites, shorter survival time was observed for aggressive tumor like lung cancer compared to patients having less aggressive primary tumor like breast and prostatic cancer. Conclusion: Spinal metastasis of unknown primary carries a diagnostic challenge to the clinician, it is possible to detect the primary site in the majority of patients if we follow optimal diagnostic strategies. Detection of primary tumor site could help the clinician to provide the best therapeutic strategies.

Utility of Fine-Needle Aspiration Cytology in Diagnosis of Cutaneous and Subcutaneous Metastasis

Introduction: Cutaneous metastasis (CM) is an uncommon clinical presentation and poses trouble in diagnosis. However, it is remarkable and can occur due to a known or an unknown primary tumor. Despite the fact that clinical assessment helps in the diagnosis, Fine-needle aspiration cytology (FNAC) is a modest, basic, and quick principle line of investigation for the finding of CM. Materials and Methods: It was a retrospective study conducted in the department of pathology at a tertiary care teaching hospital. The study was conducted from January 2010 to May 2020. All cases of CM that has been diagnosed by FNAC were included. Results: During the study period, a total of 37 cases of CM were observed, constituting 0.15% of all FNACs. The age of the patients ranged from 35 to 74 years, and the male: female ratio was 1.05:1. Primary tumor was known in all 37 cases. Among males, lung carcinoma was the more common whereas breast was the most common organ of primary among females. The most common lesion was a single nodule (27 cases), with predominant site being chest wall (32.5%), and the most common tumor at microscopy was metastatic adenocarcinoma. Conclusion: FNAC is a fast and safe procedure that can be utilized as a first line of investigation in diagnosing metastatic skin lesions. Basic assessment of cytomorphology alongside significant clinical subtleties could help in recognizing the site of an unknown primary.

Role of PET/CT and Therapy Management of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine neoplasms (panNENs) are heterogeneous neoplasms with neuroendocrine differentiation that show peculiar clinical and histomorphological features, with variable prognosis. In recent years, advances in knowledge regarding the pathophysiology and heterogeneous clinical presentation, as well as the availability of different diagnostic procedures for panNEN diagnosis and novel therapeutic options for patient clinical management, has led to the recognition of the need for an active multidisciplinary discussion for optimal patient care. Molecular imaging with positron emission tomography/computed tomography (PET/CT) has become indispensable for the management of panNENs. Several PET radiopharmaceuticals can be used to characterize either panNEN receptor expression or metabolism. The aim of this review is to offer an overview of all the currently used radiopharmaceuticals and of the new upcoming tracers for pancreatic neuroendocrine tumors (panNETs), and their clinical impact on therapy management. [68Ga]Ga-DOTA-peptide PET/CT (SSA-PET/CT) has high sensitivity, specificity, and accuracy and is recommended for the staging and restaging of any non-insulinoma well-differentiated panNEN cases to carry out detection of unknown primary tumor sites or early relapse and for evaluation of in vivo somatostatin receptors expression (SRE) to select patient candidates for peptide receptor radiometabolic treatment (PRRT) with 90Y or 177Lu and/or cold analogs. SSA-PET/CT also has a strong impact on clinical management, leading to a change in treatment in approximately a third of the cases. Its role for treatment response assessment is still under debate due to the lack of standardized criteria, even though some semiquantitative parameters seem to be able to predict response. [18F]FDG PET/CT generally shows low sensitivity in small growing and well-differentiated neuroendocrine tumors (NET; G1 and G2), while it is of utmost importance in the evaluation and management of high-grade NENs and also provides important prognostic information. When positive, [18F]FDG PET/CT impacts therapeutical management, indicating the need for a more aggressive treatment regime. Although FDG positivity does not exclude the patient from PRRT, several studies have demonstrated that it is certainly useful to predict response, even in this setting. The role of [18F]FDOPA for the study of panNET is limited by physiological uptake in the pancreas and is therefore not recommended. Moreover, it provides no information on SRE that has crucial clinical management relevance. Early acquisition of the abdomen and premedication with carbidopa may be useful to increase the accuracy, but further studies are needed to clarify its utility. GLP-1R agonists, such as exendin-4, are particularly useful for benign insulinoma detection, but their accuracy decreases in the case of malignant insulinomas. Being a whole-body imaging technique, exendin-PET/CT gives important preoperative information on tumor size and localization, which is fundamental for surgical planning as resection (enucleation of the lesion or partial pancreatic resection) is the only curative treatment. New upcoming tracers are under study, such as promising SSTR antagonists, which show a favorable biodistribution and higher tumor-to-background ratio that increases tumor detection, especially in the liver. [68Ga]pentixafor, an in vivo marker of CXCR4 expression associated with the behavior of more aggressive tumors, seems to only play a limited role in detecting well-differentiated NET since there is an inverse expression of SSTR2 and CXCR4 in G1 to G3 NETs with an elevation in CXCR4 and a decrease in SSTR2 expression with increasing grade. Other tracers, such as [68Ga]Ga-PSMA, [68Ga]Ga-DATA-TOC, [18F]SiTATE, and [18F]AlF-OC, are also under investigation.

Labeling efficiency of Tb3+ conjugated CD133 monoclonal antibody nanocomplex targeting in vitro metastatic cancer cells

Efficient cancer treatment remains a huge challenge worldwide. As reported by the World HealthOrganization, the number of cancer patients is estimated to be 24 million in 2035, which is a 70% increasecompared to 14.1 million in 2012. The severity of cancer is due to the presence of cancer stem cells (CSCs),which are directly related to drug resistance, metastasis, and tumor relapse. Because of the unknown location ofthe primary tumor and/or the residency of CSCs, standard therapies deliver a high dose of drugs to the whole body,which can have negative effects and deadly consequences for patients undergoing treatment. Therefore, efficientluminescent materials for labeling and tracking CSCs are urgently needed to determine their distribution andtarget treatment. Herein, a fluorescent Tb3+ nano-ion and CD133 monoclonal antibody (mAb) were conjugatedinto a nano probe-complex (ET2). Tb3+ nano-ion is a rare-earth element and the CD133 mAb targets CD133,which is a CSC surface marker. The Tb3+ nanorods were surface treated with silica and activated with -NH2 forfunctioning before being coupled with CD133 mAb. Strong fluorescent Tb3+ nanorods were used to decrease thetoxicity of high-dose medicines, and the purpose of the CD133 mAb was to increase the specific binding capacityof CSCs to the ET2 nanocomplex. The luminescent properties of this coupled ET2 complex were determinedand its ability to target and label CSCs was determined using the pluripotent human embryonic carcinoma cellline, NTERA-2. Fluorescence microscopy showed strong luminescent signals from ET2-exposed NTERA-2cells. It was also demonstrated that the ET2 nanocomplex effectively labeled up to 97.74% of the tested NTERA-2 cells, but only 2.35% of CCD-18Co human colon normal cells. Therefore, these results show that the ET2luminescent nanocomplex specifically targeted and labeled CSCs, and may be used for further applications infundamental and clinical research.

BT-09 Anhidrosis in neurohypophyseal germinoma treated with CBDCA and VP-16

Introduction: Acquired generalized anhidrosis (AGA) is the disease with non-congenital, non-segmented diffuse sweating dysfunction and is associated with neurological signs and dysautonomia except for anhidrosis. Here we have experienced 2 cases of AGA in the patient with neurohypophyseal germinoma after carboplatin (CBDCA) plus etoposide (VP-16) (CARE) therapy. Relationship of AGA to neurohypophyseal germinomas and their treatment is discussed. Cases: We experienced two young (26 y/o and 27 y/o) female neurohypophyseal germinoma cases of anhidrosis. They received CARE as chemotherapy and whole ventricular irradiation. They showed heat retention 2 to 3 years after initial treatment without recurred germinoma. Because acetylcholine sweating test was negative and skin biopsy revealed normal sweat gland structure, the diagnosis of acquired idiopathic generalized anhidrosis (AIGA), idiopathic pure sudomotor failure subtype, was initially made. After steroid pulse therapy, sweat function recovered partially and completely. Discussion: AIGA and germinoma are both rare diseases. So, the present 2 cases have similar clinical settings, that anhidrosis may not be idiopathic but secondary. Affected responsible site of anhidrosis in the present cases is thought to be acetylcholine receptor in the sweat cells. The present cases did not have any known disease with anhidrosis and did not receive any medication which cause anhidrosis written in the statement of the virtues of a medicine. Commonly used drugs in both cases are infusion solutions, CARE and related drugs, hormone stimulating test agents. Recently anhidrosis is reported in a case of cancer of unknown primary tumor site after using CBDCA and PTX. Both of the present cases are used CBDCA, which may cause anhidrosis. Conclusion: CBDCA may attributed to the occurrence of AGA based on hypothalamic vulnerability.

Pivotal role of PET/CT in characterization of occult metastasis with undetermined origin

BackgroundThe purpose of this multicenter diagnostic accuracy test study was conducted to assess the role of positron emission tomography/computed tomography in the detection of primary tumor in cases of metastasis of undetermined primary site, to estimate its capability in detecting additional lesions as well as evaluating disease burden and staging. This multicentric diagnostic accuracy test study included 175 patients with pathologically proven, radiologically, and/or clinically suspected metastatic lesions of undetermined primary site. Clinical, surgical, and histopathologic findings and correlative imaging modalities were used to assess the results of PET/CT; the accuracy of PET/CT was expressed in terms of sensitivity and specificity, positive and negative predictive values.ResultsThe study included 175 patients; PET-CT-positive lesions suggestive of primary malignant tumors were detected in 105 out of 175 patients. These lesions were pathologically proven to be malignant (true positive) in 100/175 patients (57.1%). Five out of 175 patients (2.9%) proved to be falsely positive after pathologic assessment; 70 out of 175 patients (40%) were negative for detection of primary malignancy all over the body by PET/CT (true negative) with no false negative results. PET/CT achieved a sensitivity of 100%, and specificity of 93.3% in detection of unknown primary tumor location.ConclusionPET/CT is an effective modality for early detection of the primary tumor site in patients with cancer of undetermined primary (CUP) which facilitates early selection of appropriate treatment protocols that will improve patients’ prognosis.

Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents.

Simple SummaryBrain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. In up to 15% of patients with BM, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. The aim of this review is to summarize current evidence on the diagnosis and treatment of BM-CUP.Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. BMs may be the cause of the neurological presenting symptoms in patients with otherwise previously undiagnosed cancer. In up to 15% of patients with BMs, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). CUP has an early and aggressive metastatic spread, poor response to chemotherapy, and poor prognosis. The pathogenesis of CUP seems to be characterized by a specific underlying pro-metastatic signature. The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. Advances in diagnostic tools, molecular characterization, and target therapy have shifted the paradigm in the approach to metastasis from CUP: while earlier studies stressed the importance of finding the primary tumour and deciding on treatment based on the primary diagnosis, most recent studies focus on the importance of identifying targetable molecular markers in the metastasis itself. The aim of this review is to summarize current evidence on BM-CUP, from the diagnosis and pathogenesis to the treatment, with a focus on available studies and ongoing clinical trials.