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Introduction: This systematic review aims to evaluate the role of biopsies in non‐oropharyngeal subsites in patients with cervical metastasis from head and neck squamous cell carcinoma of unknown primary (HNSCCUP). Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. Articles that encompassed non‐oropharyngeal biopsies in HNSCCUP as part of the diagnostic work‐up were selected and analysed. Results: A comprehensive search strategy was used to search relevant literature in PubMed from inception to October 2021. Eleven articles out of 860 were included, comprising 990 patients. There are no randomised control trials comparing the outcomes of survival and or locoregional control between patients who have or have not undergone non‐targeted biopsies of non‐oropharyngeal sub‐sites for HNSCCUP. Several retrospective studies which showed an extremely low yield from random biopsies (range of yield, 0%–9%) of non‐oropharyngeal subsites. Even targeted biopsies showed a low yield (range of yield, 0.6%–16.6%) from non‐oropharyngeal subsites. The primary site identified for Epstein–Barr virus (EBV) positive cervical lymph nodes with an unknown primary is mainly the nasopharynx (51.7%). Narrow band imaging (NBI) (sensitivity range, 64%–91%) helps in the detection of primaries to target biopsies in non‐oropharyngeal subsites. Conclusions: On the basis of this systematic review, it is not appropriate to offer biopsies of clinically and radiologically normal upper aerodigestive tract mucosa at non‐oropharyngeal sites. Offer nasopharyngeal biopsies when the cervical node sampling reveals EBV‐positive metastasis. Where available, NBI should be used to help detect and target biopsies in non‐oropharyngeal subsites. [ABSTRACT FROM AUTHOR]

Objective: As the majority of oropharyngeal squamous cell carcinoma (OPSCC) is diagnosed in males, outcomes among females are not well‐characterized. We identify sex‐specific factors in OPSCC to refine female prognostication. Study Design: Retrospective cohort. Setting: National Cancer Database (NCDB). Methods: OPSCC cases from the 2004 to 2019 NCDB were identified. Sociodemographic, clinical, and treatment characteristics (including timing between diagnosis and treatment administration) were compared between sexes. Multivariable Cox proportional hazard regression models were constructed to characterize survival in overall and female‐only cohorts. Similar multivariable binomial logistic regression and survival models were constructed to assess odds of treatment delays and their effects on survival, respectively. Results: A total of 192,973 OPSCC patients were identified; 36,695 (19%) were female. Females had more human papillomavirus (HPV) negative, lower clinical T and N stage, and higher comorbidity disease. Females experienced lower survival in HPV negative (hazard ratio, HR = 1.11, P <.001) but not HPV‐positive disease. Females were more likely to have any treatment initiated over the median of 28 days (odds ratio, OR = 1.04, P =.014) or delays in adjuvant radiotherapy initiation over 6 weeks (OR = 1.11, P =.032). Treatment delay over 60 days (HR = 1.17, P =.016) and delay in adjuvant therapy initiation (HR = 1.24, P =.02) were associated with worse survival among females. Conclusion: In one of the largest analyses of OPSCC, females had poorer survival than males, specifically in HPV‐negative disease, despite presentation with less advanced disease. Notably, delays in any treatment initiation and adjuvant radiotherapy initiation were more likely in HPV‐negative women and associated with worse survival, highlighting potential systemic weaknesses contributing to poor prognosis among females. [ABSTRACT FROM AUTHOR]

BACKGROUND: The present study was taken up to assess the role of fine-needle aspiration cytology in diagnosing left supraclavicular lymphadenopathy and assess if the Virchow’s node still has the same clinical corollaries in recent times, where there has been a drastic change in epidemiology and therapy of cancers. Material and Methods: The present study is a 3-year retrospective analytical study conducted in the department of pathology in a tertiary care teaching hospital. RESULTS: A total number of 106 cases were received during the study period. The mean age of presentation was 45.86 ± 17.71 years, and the male-to-female incidence of 0.65. Malignant pathology outnumbered benign pathology. The most common malignant pathology was metastatic deposits. The most common primary malignancy was breast carcinoma in females and lung carcinoma in males. CONCLUSION: With the changing epidemiology of cancers, left supraclavicular nodes can be more commonly involved by supradiaphragmatic malignancies when compared to the yesteryears.

Purpose: To conduct a comprehensive narrative review of the evidence for radiotherapy target volumes to the neck, after neck dissection, for head and neck squamous cell carcinoma from an unknown primary (HNSCCUP). Inclusion or exclusion of mucosal irradiation is not the focus of interest for this review article. Materials and Methods: Literature (PubMed‐Medline, EMBASE database and Cochrane library) was searched using the relevant keywords. The search results were limited to the studies published in year 2000 or after. Results: Eight studies met the inclusion criteria. All studies were retrospective in nature. The incidence of contralateral recurrence rates in the untreated neck when the involved neck only is treated remains very low (0%–10%). Survival has improved over the past two decades, most likely due to improved diagnostic techniques and the increase in incidence of HPV‐related disease. Conclusion: Given the rarity of disease, level one evidence from randomised controlled trials is lacking. Available data are retrospective but support unilateral post‐operative radiotherapy as a treatment option in selected cases. [ABSTRACT FROM AUTHOR]

Background: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical–pathological features. Methods: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. Results: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6–5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: <.001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). Conclusion: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome. [ABSTRACT FROM AUTHOR]

Introduction: Controlled randomized trials, molecular analytics, and guideline recommendations have so far been irreplaceable tools to ensure appropriate treatment and decision-making for physicians and patients. Individual patient models are increasingly complementing these methods, particularly in the case of advanced cancers, rare cancers, and cancers of unknown primary (CUP), as in these cases comprehensive clinical evidence is unavailable, often resulting in poor treatment success, even after stratification. Case Presentation: Here we report a 53-year-old patient with CUP with axillary lymph node metastases for whom patient-derived 3D (PD3D®) tumor organoids successfully guided personalized treatment. PD3D tumor models were used to screen drugs that are effective at the suspected primary tumor site. The screen revealed sensitivity to doxorubicin, which is not indicated for CUP treatment but hinted toward breast cancer that was subsequently confirmed as triple-negative breast cancer (TNBC). The patient showed partial remission to first-line doxorubicin and cyclophosphamide, which were followed by docetaxel. Subsequent radiotherapy eventually led to a complete remission, which is still ongoing. Conclusion: We conclude that pre-therapeutic drug sensitivity screening with PD3D tumor models can be essential in guiding and enabling an effective personalized treatment for patients with hard-to-treat cancers, like CUP or TNBC.

Background Patients with Metastatic Bone Disease (MBD) often present with complaints of pain and multiple osteolytic lesions findings. Remarkably, 30% of these cases exhibit an undetected primary lesion. Hence, categorizing them as MBD of unknown origin. The diagnostic processes of patients with MBD of unknown origin typically takes up to four months, rendering it as a catastrophic disease with the second-highest financial burden. Given its urgency, it is necessary to develop a evidence-based consensus for managing cases of MBD with an unknown origin. Purpose This study aimed to enhance the effectiveness and efficiency of treating patients with MBD of unknown origin through the application of the INA-MBD algorithm. Research method A quasi-experimental study with a pretest and post-test design was conducted with a total of 128 patients who met the inclusion and exclusion criteria. The patients were consecutively enrolled and categorized into two groups: the intervention group with the INA-MBD algorithm and the non-intervention group without the INA-MBD algorithm. The primary outcomes were the cost and time to diagnose MBD of unknown origin. The proposed measuring tool was the INA-MBD algorithm. Furthermore, for the cost-to-diagnosis variable, an extra measurement tool was used, which were summaries of the patient’s medical bill including hospital stays and medical procedures. The analysis of data related to the time-to-diagnosis variable was conducted using the Log Rank regression test, and cost-to-diagnosis variable was carried out using co-variance test.

BACKGROUND: Previous studies report increasing cholangiocarcinoma (CCA) incidence up to 2015. This contemporary retrospective analysis of CCA incidence and mortality in the US from 2001-2017 assessed whether CCA incidence continued to increase beyond 2015. PATIENTS AND METHODS: Patients (≥18 years) with CCA were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results 18 cancer registry (International Classification of Disease for Oncology [ICD-O]-3 codes: intrahepatic [iCCA], C221; extrahepatic [eCCA], C240, C241, C249). Cancer of unknown primary (CUP) cases were identified (ICD-O-3: C809; 8140/2, 8140/3, 8141/3, 8143/3, 8147/3) because of potential misclassification as iCCA. RESULTS: Forty-thousand-and-thirty CCA cases (iCCA, n=13,174; eCCA, n=26,821; iCCA and eCCA, n=35) and 32,980 CUP cases were analyzed. From 2001-2017, CCA, iCCA, and eCCA incidence (per 100 000 person-years) increased 43.8% (3.08 to 4.43), 148.8% (0.80 to 1.99), and 7.5% (2.28 to 2.45), respectively. In contrast, CUP incidence decreased 54.4% (4.65 to 2.12). CCA incidence increased with age, with greatest increase among younger patients (18-44 years, 81.0%). Median overall survival from diagnosis was 8, 6, 9, and 2 months for CCA, iCCA, eCCA, and CUP. From 2001-2016, annual mortality rate declined for iCCA (57.1% to 41.2%) and generally remained stable for eCCA (40.9% to 37.0%) and for CUP (64.3% to 68.6%). CONCLUSIONS: CCA incidence continued to increase from 2001-2017, with greater increase in iCCA versus eCCA, whereas CUP incidence decreased. The divergent CUP versus iCCA incidence trends, with overall greater absolute change in iCCA incidence, provide evidence for a true increase in iCCA incidence that may not be wholly attributable to CUP reclassification.

BackgroundThis study evaluated whether fluorescence lifetime imaging (FLIm), coupled with standard diagnostic workups, could enhance primary lesion detection in patients with p16+ head and neck squamous cell carcinoma of the unknown primary (HNSCCUP).MethodsFLIm was integrated into transoral robotic surgery to acquire optical data on six HNSCCUP patients' oropharyngeal tissues. An additional 55-patient FLIm dataset, comprising conventional primary tumors, trained a machine learning classifier; the output predicted the presence and location of HNSCCUP for the six patients. Validation was performed using histopathology.ResultsAmong the six HNSCCUP patients, p16+ occult primary was surgically identified in three patients, whereas three patients ultimately had no identifiable primary site in the oropharynx. FLIm correctly detected HNSCCUP in all three patients (ROC-AUC: 0.90 ± 0.06), and correctly predicted benign oropharyngeal tissue for the remaining three patients. The mean sensitivity was 95% ± 3.5%, and specificity 89% ± 12.7%.ConclusionsFLIm may be a useful diagnostic adjunct for detecting HNSCCUP.

Abstract Background SMARCB1, also known as INI1, is a member of a large protein complex involved in chromatin remodeling and thus the regulation of gene expression. It is located on chromosome 22q11.2. SMARCB1 tumors have been found in various locations, including the sinonasal region, gastrointestinal tract, central nervous system (in atypical teratoid and rhabdoid tumors), and perirenal region (in malignant rhabdoid tumors) in both adults and children. Case presentation We describe here the first case in the literature of an INI1-deficient neck carcinoma without a primary tumor managed with surgical therapy and neck dissection in a young Caucasian woman of 29 years old, followed by chemotherapy before radiotherapy, with regional control after 18 months of follow-up. Histologic analysis showed an undifferentiated carcinoma without glandular or epidermoid differentiation. Biomolecular analysis of the tumor revealed a homozygous deletion of the SMARCB1 gene on RNA sequencing. Conclusion Research of INI1 deletion should be performed for undifferentiated carcinoma of young patients because of possibilities of molecular therapies such as autophagy inhibitors or proteasome inhibitors could be used in clinical trials.

Background Patients with Metastatic Bone Disease (MBD) often presenting with complaints of pain and multiple osteolytic lesions findings. Remarkably, 30% of these cases exhibit an undetected primary lesion. Hence, categorizing them as MBD of unknown origin. The diagnostic processes of patients with MBD of unknown origin typically takes up to four months, rendering it as a catastrophic disease with the second-highest financial burden. Given its urgency, it is necessary to develop a systematic and evidence-based consensus for managing cases of MBD with an unknown origin. Purpose This study aimed to enhance the effectiveness and efficiency of treating patients with MBD of unknown origin through the application of the INA-MBD algorithm. Research method A quasi-experimental study with a pretest and post-test design was conducted with a total of 128 patients who met the inclusion and exclusion criteria. The patients were consecutively enrolled and categorized into two groups: the intervention group with the INA-MBD algorithm and the non-intervention group without the INA-MBD algorithm. The primary outcomes were the cost and time to diagnose MBD of unknown origin. The proposed measuring tool was the INA-MBD algorithm. Furthermore, for the cost-to-diagnosis variable, an extra measurement tool was used, which were summaries of the patient’s medical bill including hospital stays and medical procedures. The analysis of data related to the time-to-diagnosis variable was conducted using the Log Rank regression test, and cost-to-diagnosis variable was carried out using co-variance test.

Introduction: Controlled randomized trials, molecular analytics, and guideline recommendations have so far been irreplaceable tools to ensure appropriate treatment and decision-making for physicians and patients. Individual patient models are increasingly complementing these methods, particularly in the case of advanced cancers, rare cancers, and cancers of unknown primary (CUP), as in these cases comprehensive clinical evidence is unavailable, often resulting in poor treatment success, even after stratification. Case Presentation: Here we report a 53-year-old patient with CUP with axillary lymph node metastases for whom patient-derived 3D (PD3D®) tumor organoids successfully guided personalized treatment. PD3D tumor models were used to screen drugs that are effective at the suspected primary tumor site. The screen revealed sensitivity to doxorubicin, which is not indicated for CUP treatment but hinted toward breast cancer that was subsequently confirmed as triple-negative breast cancer (TNBC). The patient showed partial remission to first-line doxorubicin and cyclophosphamide, which were followed by docetaxel. Subsequent radiotherapy eventually led to a complete remission, which is still ongoing. Conclusion: We conclude that pre-therapeutic drug sensitivity screening with PD3D tumor models can be essential in guiding and enabling an effective personalized treatment for patients with hard-to-treat cancers, like CUP or TNBC. [ABSTRACT FROM AUTHOR]

Background: SMARCB1, also known as INI1, is a member of a large protein complex involved in chromatin remodeling and thus the regulation of gene expression. It is located on chromosome 22q11.2. SMARCB1 tumors have been found in various locations, including the sinonasal region, gastrointestinal tract, central nervous system (in atypical teratoid and rhabdoid tumors), and perirenal region (in malignant rhabdoid tumors) in both adults and children. Case presentation: We describe here the first case in the literature of an INI1-deficient neck carcinoma without a primary tumor managed with surgical therapy and neck dissection in a young Caucasian woman of 29 years old, followed by chemotherapy before radiotherapy, with regional control after 18 months of follow-up. Histologic analysis showed an undifferentiated carcinoma without glandular or epidermoid differentiation. Biomolecular analysis of the tumor revealed a homozygous deletion of the SMARCB1 gene on RNA sequencing. Conclusion: Research of INI1 deletion should be performed for undifferentiated carcinoma of young patients because of possibilities of molecular therapies such as autophagy inhibitors or proteasome inhibitors could be used in clinical trials. [ABSTRACT FROM AUTHOR]

Background and Purpose: Squamous cell carcinoma of unknown primary (SCC-CUP) of the head and neck region remains a clinical challenge, with uncertainty surrounding the necessity of contralateral irradiation of cervical lymphatic drainage in cases of unilateral involvement. Materials and Methods: A retrospective study was conducted at the Department of Radiation Oncology, University Medical Center Mainz, on a cohort of 50 patients with unilateral SCC-CUP of the head and neck region treated between 2005 and 2019. 30 patients received bilateral and 20 received unilateral cervical radiotherapy. The majority (n = 38, 76 %) were treated with modern IMRT/ VMAT (Intensity-modulated Radiation Therapy/ Volumetric Modulated Arc Therapy) techniques. Results: After a median follow-up of 64.5 months, locoregional recurrences occurred in 26 % of cases (n = 13/50), all of which were ipsilateral and predominantly within the volume of the previous irradiated CTV (clinical target volume) (85 %, n = 11/13). No patient treated unilaterally developed a contralateral recurrence in the neck. After 3 years, we observed 7 locoregional recurrences in the bilateral irradiated group (n = 7/30, 23 %), and 5 locoregional recurrences in the unilateral irradiated group (n = 5/20, 25 %). After 3 years, 12 patients had died in the bilateral irradiated group (n = 12/30, 40 %), and 7 in the unilateral irradiated group (n = 7/20, 35 %). 7 Patients showed distant metastases after 3 years in the bilateral irradiated group (n = 7/30, 23 %), and 2 in the unilateral irradiated group (n = 2/20, 10 %). Locoregional control (LRC) at 5 years was 66.2 % in the bilaterally irradiated group, and 70.0 % in the unilaterally irradiated group. Overall survival (OS) was 52.6 % (bilateral) and 64.0 % (unilateral). Distant metastasis-free survival (DMFS) was 74.7 % (bilateral) and 84.4 % (unilateral). No significant differences were observed in OS (p = 0.37), LRC (p = 0.91), and DMFS (p = 0.91) between the groups.Acute toxicity ≥ °2 accordingly CTCAE (Common Terminology Criteria of Adverse Events) was high with 97% while late toxicity ≥ °2 was moderate with 31%. There was no statistically significant difference between the group of unilateral and bilateral irradiated patients. Conclusion: These data suggest that contralateral cervical irradiation may be of limited benefit in patients with SCC-CUP, as recurrences occured ipsilaterally, and predominantly within the area of prior irradiation. Unilateral irradiation seems to be adequate for carefully selected patients.

Malignant melanoma (MM) frequently occurs in the skin or mucosa, whereas malignant melanoma of unknown primary (MUP) is diagnosed in patients with lymph nodes or visceral organs as the site of origin, where it is challenging to detect the primary lesion by comprehensive examination. MUP is possibly related to the spontaneous regression of the primary lesion. In addition, primary hepatic melanoma (PHM) usually refers to the primary MM occurring in the liver, with no typical primary lesions and no manifestations of tumor metastasis. A 61-year-old male patient with liver as the site of origin was diagnosed with MM by Melan-A, HMB-45, and S-100 immunohistochemistry staining of liver biopsy tissue. Based on a comprehensive examination, no basis was found for melanoma in sites such as the skin, mucosa, five sense organs, brain, digestive tract, respiratory tract, or genitalia, and the patient was subsequently diagnosed with MUP. MMs require a comprehensive inspection, beginning with the liver, to search for the primary lesion; if the primary lesion is not found, the possibility of PHM or MUP should be considered.

Mature teratoma is a common tumor that can undergo malignant transformation, either in ovarian or extragonadal sites. While adenocarcinoma superimposed on sacrococcygeal teratoma is rare, mucinous variants have been reported in only five cases. Here, we present a case of a young girl with disseminated metastasis of mucinous carcinoma, initially of unknown primary origin. Further investigation by a dedicated multidisciplinary team (MDT) revealed a focus of mucinous carcinoma (intestinal type) in a sacrococcygeal teratoma incompletely resected five years earlier. The patient is currently undergoing second-line chemotherapy after experiencing side-effects on the first-line regimen. Pathologists, gynecologic oncologists, and surgical oncologists should exercise caution when dealing with locally aggressive teratomas, thoroughly searching for malignant components and conducting short-term follow-up.

BackgroundMelanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared with those with known primary melanoma enrolled in the E1609 adjuvant trial that tested ipilimumab at 3 and 10 mg/kg vs high-dose interferon-alfa (HDI).Patients and methodsMUP status was defined as initial presentation with cutaneous, nodal or distant metastasis without a known primary. Relapse-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Gene expression profiling (GEP) was performed on the tumor biopsies of a subset of patients. Similarly, peripheral blood samples were tested for candidate soluble and cellular immune biomarkers.ResultsMUP cases represented 12.8% of the total population (N=1699) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, RFS (p=0.001) and overall survival (OS) (p=0.009) showed outcomes significantly better for patients with unknown primary. The primary tumor status remained prognostically significant after adjusting for treatment and stage in multivariate Cox proportional hazards models. Including only ipilimumab-treated patients, RFS (p=0.005) and OS (p=0.023) were significantly better in favor of those with unknown primary. Among patients with GEP data (n=718; 102 MUP, 616 known), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the MUP tumors compared with known primaries. Further investigation into infiltrating immune cell types estimated significant enrichment with CD8 +and CD4+T cells, B cells and NK cells as well as significantly higher major histocompatibility complex (MHC)-I and MHC-II scores in MUP compared with known primary. Among patients tested for circulating biomarkers (n=321; 66 unknown and 255 known), patients with MUP had significantly higher circulating levels of IL-2R (p=0.04).ConclusionPatients with MUP and high-risk melanoma had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of MUP as a distinct prognostic marker in patients with high-risk melanoma.

Squamous cell carcinoma of unknown primary (SCCUP) accounts for up to 5%1-4 of cancers in the head and neck region and are defined as "metastatic disease in the lymph nodes of the neck without any evidence of a primary tumour of the upper aerodigestive tract"5. It typically presents as a painless neck lump and, as a diagnosis of exclusion, requires extensive investigation. Due to the rarity of SCCUP, management is largely determined by individual institutions depending on local experience and expertise. Much debate in the literature currently centres on management of the ipsilateral versus bilateral adjuvant neck and irradiation of the site of potential primary. Current practice is evolving nationally due to improved radiotherapy techniques and knowledge of long-term outcomes of dysphagia and aspiration at risk structures (DARS) irradiation. In addition, the integration of procedures such as Transoral Robotic Surgery (TORS) mucosectomy into the pathway with a view to addressing the diagnostic void is emerging. It is anticipated that updated US ASCO guidelines and RCR consensus statement when published will assist. In our centre, treatment typically involves surgery to neck followed by adjuvant radiotherapy to the cervical nodal regions and ipsilateral oropharynx with or without chemotherapy. This study reports our long term outcomes following this treatment. Electronic notes were reviewed retrospectively of patients diagnosed from 2007-2019 with SCCUP. All patients included were staged as Tx M0, (TNM 7), and treated with radical intent and neck dissection. Patient demographics, tumour characteristics, treatment details and outcomes were collated. Eighty two patients were identified, 75 patients underwent unilateral neck dissection, one patient had excision biopsy of the neck and 6 patients underwent bilateral neck dissection. Median age at presentation was 60 years, 71 were male; p16 status was available for 41 patients, 32 positive and 9 negative. The commonest staging was Tx N2b M0 in 40 patients. Median follow up of 6.5 years. Sixty three patients received adjuvant treatment; 32 patients with radiotherapy and concurrent chemotherapy and 31 patients with radiotherapy alone. Loco-regional control rate was 76%. Four patients (6.3%) developed mucosal emergence, 8 patients (13%) developed nodal recurrence and 6 patients developed distant metastases (9.5%). Nineteen patients had no adjuvant treatment. Loco-regional control rate was 42%. Nine patients (47%) developed mucosal emergence, most common site was ipsilateral tongue base in 6 patients (67%). Of these 9 patients, 6 also developed neck recurrence. One patient developed neck recurrence alone and underwent further surgery followed by post-operative radiotherapy. Two patients developed distant metastases. Neck recurrence rate was higher when patients had no adjuvant treatment following surgery (37% vs 12%). Primary mucosal emergence was also higher in patients who did not receive adjuvant treatment (47% vs 6.3%). Contra lateral neck recurrence occurred in 2 patients (3.1%) following ipsilateral adjuvant treatment. Surgery to neck followed by adjuvant radiotherapy with or without chemotherapy to neck and ipsilateral oropharynx in patients with SCCUP offers excellent rates of loco regional control. Our data supports the use of ipsilateral neck radiotherapy, showing low rates of contra-lateral recurrence. Radiotherapy to potential primary was associated with low rates of mucosal emergence. The high rate of primary mucosal emergence and local neck failure in patients without adjuvant radiotherapy supports its integral role in long-term loco-regional control. More work needs to be done to establish the role of TORS in the management of these patients. [ABSTRACT FROM AUTHOR]

Mature teratoma is a common tumor that can undergo malignant transformation, either in ovarian or extragonadal sites. While adenocarcinoma superimposed on sacrococcygeal teratoma is rare, mucinous variants have been reported in only five cases. Here, we present a case of a young girl with disseminated metastasis of mucinous carcinoma, initially of unknown primary origin. Further investigation by a dedicated multidisciplinary team (MDT) revealed a focus of mucinous carcinoma (intestinal type) in a sacrococcygeal teratoma incompletely resected five years earlier. The patient is currently undergoing second-line chemotherapy after experiencing side-effects on the first-line regimen. Pathologists, gynecologic oncologists, and surgical oncologists should exercise caution when dealing with locally aggressive teratomas, thoroughly searching for malignant components and conducting short-term follow-up. [ABSTRACT FROM AUTHOR]

Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP). Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP). Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS). Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively. Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied. [ABSTRACT FROM AUTHOR]

Purpose: To compare the prognosis of patients with axillary adenocarcinoma from an unknown primary (ACUPax) origin with negative MRI results and those with MRI-detected primary breast cancers. Materials and Methods: The breast MRI images of 32 patients with ACUPax without signs of primary breast cancer on mammography and ultrasound (US) were analyzed. Spot compression-magnification mammography and second-look US were performed for the area of MRI abnormality in patients with positive results; any positive findings corresponding to the MRI abnormality were confirmed by biopsy. If suspicious MRI lesions could not be localized on mammography or US, MR-guided biopsy or excision biopsy after MR-guided localization was performed. We compared the prognosis of patients with negative breast MRI with that for patients with MRI-detected primary breast cancers. Results: Primary breast cancers were confirmed in 8 (25%) patients after breast MRI. Primary breast cancers were not detected on MRI in 24 (75%) patients, including five cases of false-positive MRI results. Twenty-three patients underwent axillary lymph node dissection (ALND) followed by whole breast radiation therapy (WBRT) and chemotherapy (n=17) or subsequent chemotherapy only (n=2). Recurrence or distant metastasis did not occur during follow up in 7/8 patients with MRI-detected primary breast cancers and 22/24 patients with negative MRI results. Regional recurrence or distant metastasis did not occur in any MR-negative patient who received adjuvant chemotherapy after ALND and WBRT. Conclusion: The prognoses of MR-negative patients with ACUPax who received ALND and WBRT followed by chemotherapy were as good as those of patients with MRI-detected primary breast cancers. [ABSTRACT FROM AUTHOR]

Importance: Squamous cell carcinoma without a known primary is an uncommon form of head and neck cancer that requires multidisciplinary collaboration for effective management. Objective: To evaluate the quality of clinical practice guidelines (CPG) using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. Design: A systematic literature search was performed to identify CPGs pertaining to the diagnosis and treatment of head and neck squamous cell carcinoma of unknown primary (HNSCCUP). Data were abstracted from guidelines meeting inclusion criteria and appraised by four independent reviewers in the six domains of quality defined by the AGREE II. Setting: Online database. Participants: None. Exposure: None. Main outcome(s) and measure(s): Quality domain scores and intraclass correlation coefficients (ICC) were calculated across domains to qualify inter-rater reliability. Results: Seven guidelines met inclusion criteria. Two guidelines achieved a score of > 60% in five or more AGREE II quality domains to gain designation as 'high'-quality content. One "average-quality" guideline authored by the ENT UK Head and Neck Society Council achieved a score of > 60% in three quality domains. The remaining four CPGs demonstrated low-quality content, with deficits most pronounced in domains 3 and 5, suggesting a lack of rigorously developed and clinically applicable information. Conclusions and relevance: As the diagnosis and treatment of head and neck cancer continues to evolve, identification of high-quality guidelines will become increasingly important. The authors recommend consulting HNSCCUP guidelines from the National Institute for Health and Care Excellence (NICE) or the American Society of Clinical Oncology (ASCO). Trial registration: None. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Carcinoma of unknown primary (CUP) is a diverse category of malignancies diagnosed in patients who have metastatic disease but without an identifiable primary tumor at initial presentation. Case Report: We report a case of CUP which was later diagnosed to be metastatic adenocarcinoma of the breast in a 62-yearold woman. The patient initially presented to a primary care clinic with an incidental finding of a small hard mass in the middle of the sternum, with no other clinical findings in the breast or axillary lymph nodes. Chest X-ray, ultrasound, and CT scan of the sternum suggested a benign sternal lesion, and a mammogram was normal. Due to the persistence of the mass, a biopsy was performed. The histopathological findings revealed a metastatic adenocarcinoma, most likely from breast origin, with positive estrogen receptor (ER) and mammaglobin on immunohistochemistry studies. The patient subsequently underwent PET scan, repeat mammogram, and MRI of the breast. Following high uptake in the rectum on PET, a colonoscopy was performed, revealing a suspicious rectal mass. The mass was surgically excised, and the final histopathological examination concluded the mass was a second primary adenocarcinoma of the rectum. Genetic analyses for BRCA1 and BRCA2 were negative. Conclusions: This is a rare case of an isolated bone-like lesion on the sternum due to metastatic adenocarcinoma of the breast in a patient with no prior history of breast cancer and lacking any clinical or radiological evidence of breast or axillary lymph node lesions on presentation. The patient was also subsequently diagnosed with 2 primary carcinomas. Thorough clinical examination, extensive radiological investigations, laboratory investigations, histopathological examination, and a multidisciplinary approach are essential in managing CUP. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) is a rare malignancy that presents with metastatic disease and no identifiable site of origin. Most patients have unfavorable features and attempts to treat based on tissue-of-origin identification have not yielded a survival advantage compared with empiric chemotherapy. Next-generation sequencing has revealed genomic alterations that can be targeted in selected cases, suggesting that CUP represents a unique malignancy in which the genomic aberrations may be integral to the diagnosis. Recent trials focusing on tailored combination therapy matched to the genomic alterations in each cancer are providing new avenues of clinical investigation. Here, we discuss recent findings on molecular aberrations in CUP and how the genomic and immune landscape can be leveraged to optimize therapy.

Abstract Background CDX2, a homeobox gene is the marker of intestinal differentiation. Its expression may lead to misdiagnosis while evaluating metastasis from unknown primary. In the present narrative, we discuss the clinical, morphological, and immunohistochemical (IHC) findings of metastatic adenocarcinoma of the lymph node that displayed nuclear immunoexpression of CDX2. However, the clinical and radiological picture supported the non-intestinal primary; prostate in one and lung in the other. Case presentation A 68-year-old man presented cervical lymph node enlargement. An epithelial tumor with acinar and cribriform pattern was seen that showed expression of CK, CDX2, and PSA in IHC. The patients complained of nonspecific symptoms related to both the gastrointestinal system and the prostate. Serum PSA was diagnostic (> 500 ng/ml). Similarly, core biopsy from mediastinal lymph node from a 51-year-male was received with possible differential of cancer and tuberculosis. Moderately differentiated adenocarcinoma was observed with the expression of EMA, CK 7, CDX2, and TTF1. The expression of both CDX2 and TTF1 was patchy. When the patient was called and all the details were sought the computed tomography (CT) thorax showed a lower chest wall lesion and multiple metastasis. The case was hence signed off as primary from lung on basis of clinical picture. Conclusion Such deviants must be reported and recorded. The knowledge of these will make a pathologist cautious and thus avoid misdiagnosis.

Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP).

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Background: Differentiated thyroid cancer is the commonest endocrine malignancy. Mortality in the presence of distant metastasis can increase dramatically. Bony metastasis often leads to increased morbidity and mortality. We report a case of a 60-year-old male who had metastatic spread of follicular cancer of the thyroid, without any identifiable primary. Case Presentation: A 60-year-old male presented with backache and weakness of lower limbs due to the collapse of the 11th thoracic vertebra. He underwent laminectomy and internal fixation. The histopathology revealed that it was the metastatic spread of follicular cancer of the thyroid. The histopathology revealed no malignancy in the thyroidectomy specimen. Subsequent administration of radioactive iodine showed a fall in thyroglobulin from 6,000 to 203 ng/ml. Conclusion: In cases of metastasis from an unknown primary, follicular thyroid cancer should be included in the differential diagnosis. Treatment after thyroidectomy can lead to good results. [ABSTRACT FROM AUTHOR]

Copyright of Die Radiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC). Methods: We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard. Results: A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUVmax, TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters). Conclusions: CT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management. [ABSTRACT FROM AUTHOR]

Objective: Tongue base mucosectomy identified cancer in 78 per cent of cancers of unknown primary in a recent meta-analysis. The carbon dioxide laser is an alternative technique if there is no access to a robot. This study aimed to describe the steps for undertaking tongue base mucosectomy using the carbon dioxide laser and its diagnostic utility in cancers of unknown primary. Method: This was a prospective feasibility study utilising carbon dioxide laser for tongue base mucosectomy in cancers of unknown primary. Data collected included demographic data and p16 status. Results: There were 14 cancers of unknown primary with 86 per cent p16 positivity on immunohistochemistry. Laser tongue base mucosectomy alone identified the cancer primary in 7 of 12 (58 per cent) cancers of unknown primary among p16 positive tumours and 0 of 2 (0 per cent) among p16 negative tumours. Combining bilateral tonsillectomy with laser tongue base mucosectomy resulted in identification of the primary cancer in 8 of 12 (67 per cent) p16 positive tumours. Conclusion: In centres without a robot, tongue base mucosectomy using the carbon dioxide laser is a viable alternative, especially in combination with bilateral tonsillectomy in p16 positive cases. [ABSTRACT FROM AUTHOR]

Head and neck cancers of unknown primary (CUP) represent up to 10% of all cancers located in the head and neck. True cancers of unknown primary, which remain of undetected primary origin after a correct clinical, imaging, surgical evaluation, have a reported frequency of between 1% and 2%. Cancers of unknown primary of the head and neck are a diagnostic challenge, considering that their main clinical manifestation is represented by the appearance of lymph node metastases in the cervical region. In general, the detection of cancers with an unknown starting point is late, difficult, with significant therapeutic failure. The diagnostic-therapeutic approach starts from the histopathological structure of the lymph node metastasis and continues with a correct and complete imaging evaluation. In this review are presented the diagnosis and therapeutic challenges and importance of head and neck cancers with unknown primary. [ABSTRACT FROM AUTHOR]

To evaluate the clinical features, molecular subtypes, therapeutic strategies, and prognostic factors of occult breast cancer (OBC). Patients with T0-3/N1-3/M0 breast cancer diagnosed in 2010–2018 (n = 114,303, including 691 with OBC) were retrieved from the Surveillance, Epidemiology, and End-Results (SEER) database. The endpoints were overall survival (OS) and breast cancer-specific survival (BCSS). Compared with non-OBC, OBC presented significantly more adverse clinicopathological prognostic features. More patients with OBC underwent breast-conserving treatment (BCT) and less had axillary lymphadenectomy (ALD). Outcomes were more favorable in OBC cases compared with non-OBC cases (p =.002 for OS, p =.002 for BCSS). Triple-negative (TNBC) and HER2-enriched were the subtypes with the worst prognosis in OBC (p <.05). Prognosis was better for triple-negative OBC compared with the same subtype of non-OBC. N-stage was not a strong prognostic indicator of OBC (p >.05 for OS). Cases who underwent systemic chemotherapy alone without surgery had the worst prognosis among OBC patients. For locoregional therapy, mastectomy and radiotherapy could confer survival advantage; standard axillary lymph node dissection (ALND) and positive lymph node dissection (PLND) contributed notably to OS in OBC patients. Both OS and BCSS were better in OBC cases compared with non-OBC. Systemic chemotherapy alone without surgery is not appropriate for OBC treatment, and mastectomy plus standard axillary surgery is recommended. Patients with hormone receptor-positive and low burden of axillary lymph node metastasis may be spared from radiotherapy after undergoing standard axillary lymphadenectomy. [ABSTRACT FROM AUTHOR]

Although the vast majority of melanomas have a primary site, 3%–4% of all melanomas in distant sites display no known primary site (MUP). This phenomenon is not fully understood and various hypotheses have been introduced. The prognostic significance of MUP has been unclear, with some studies showing no survival benefit while others find improved survival compared to stage-matched patients with melanoma of known primary site (MKP). Between 1997 and 2014, 864 patients underwent an en bloc resection of clinical nodal metastases at a referral centre for metastatic melanoma in Norway. The MUP (n = 113) and MKP (n = 751) patients were graded with stage III or IV. The overall survival (OS) was calculated with the Kaplan-Meier method, and multivariate analysis identified factors of significance for the two groups. A significant five-year OS emerged for stage III, MUP = 58% and 42% for MKP, but not for stage IV. The five-year relapse-free survival (RFS) was 41% and 31% for MUP and MKP respectively (p = 0.049). The statistically significant inter-group differences (MUP/MKP) were observed in the univariate and multivariate analyses of age, gender, number of affected nodes, tumour size and perinodal growth within stage III and tumour size within stage IV. After regional lymphadenectomy, MUP patients with clinical nodal metastases had a better outcome than MKP patients. This finding supports the theory that an endogenously mediated immune response may promote the regression of a cutaneous melanoma. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms in which tumor staging/prognosis and response to treatments depend heavily on accurate and timely identification of the anatomic primary site or NET subtype. Despite recent technological advancements and use of multiple diagnostic modalities, 10% to 14% of newly diagnosed NETs are not fully characterized based on subtype or anatomic primary site. Inability to fully characterize NETs of unknown primary may cause delays in surgical intervention and limit potential treatment options. To address this unmet need, clinical validity and utility are being demonstrated for novel approaches that improve NET subtype or anatomic primary site identification. Functional imaging using Ga-radiolabeled DOTATATE positron emission tomography/computed tomography has been shown to overcome some false-positive and resolution issues associated with octreotide scanning and computed tomography/magnetic resonance imaging. Using a genomic approach, molecular tumor classification based on differential gene expression has demonstrated high diagnostic accuracy in blinded validation studies of different NET types and subtypes. Given the widespread availability of these technologies, we propose an algorithm for the workup of NETs of unknown primary that integrates these approaches. Including these technologies in the standard workup will lead to better NET subtype identification and improved treatment optimization for patients.

Leptomeningeal carcinomatosis, leptomeningeal meningitis, or, as referred here, leptomeningeal metastasis (LM), is a rare but frequently fatal complication seen in advanced stage of cancer either locally advanced or after a metastasis of a known primary cancer. We present a rare and uncommon case of leptomeningeal metastases from carcinoma of unknown primary. A 32-year-old female was diagnosed with LM; however, no known primary carcinoma was identified after 2 separate biopsies. The first biopsy of the right pre-tracheal lymph node showed poorly differentiated pan-keratin (AE1 and AE3) and placental alkaline phosphatase with the possibility of germ cell origin. Second cytology of cervical lymphadenopathy was remarkable for cytokeratin 7 and 20, placental alkaline phosphatase, and CDX2 suggestive of germ line tumor with both mucinous ovarian and gastrointestinal carcinomas. Unfortunately, the LM progressed rapidly despite multiple cycles of germ cell origin directed systemic and intrathecal chemotherapy, and the patient opted for hospice care without getting a chance to identify the primary source.

Abstract Background Methods for developing national recommendations vary widely. The successful adoption of new guidance into routine practice is dependent on buy-in from the clinicians delivering day-to-day patient care and must be considerate of existing resource constraints, as well as being aspirational in its scope. This initiative aimed to produce guidelines for the management of head and neck squamous cell carcinoma of unknown primary (HNSCCUP) using a novel methodology to maximise the likelihood of national adoption. Methods A voluntary steering committee oversaw 3 phases of development: 1) clarification of topic areas, data collection and assimilation, including systematic reviews and a National Audit of Practice; 2) a National Consensus Day, presenting data from the above to generate candidate consensus statements for indicative voting by attendees; and 3) a National Delphi Exercise seeking agreement on the candidate consensus statements, including representatives from all 58 UK Head and Neck Multidisciplinary Teams (MDT). Methodology was published online in advance of the Consensus Day and Delphi exercise. Results Four topic areas were identified to frame guideline development. The National Consensus Day was attended by 227 participants (54 in-person and 173 virtual). Results from 7 new systematic reviews were presented, alongside 7 expert stakeholder presentations and interim data from the National Audit and from relevant ongoing Clinical Trials. This resulted in the generation of 35 statements for indicative voting by attendees which, following steering committee ratification, led to 30 statements entering the National Delphi exercise. After 3 rounds (with a further statement added after round 1), 27 statements had reached ‘strong agreement’ (n = 25, 2, 0 for each round, respectively), a single statement achieved ‘agreement’ only (round 3), and ‘no agreement’ could be reached for 3 statements (response rate 98% for each round). Subsequently, 28 statements were adopted into the National MDT Guidelines for HNSCCUP. Conclusions The described methodology demonstrated an effective multi-phase strategy for the development of national practice recommendations. It may serve as a cost-effective model for future guideline development for controversial or rare conditions where there is a paucity of available evidence or where there is significant variability in management practices across a healthcare service.

Presentation with cervical lymphadenopathy would usually have an aetiology of neoplasm, infection or reactive cause. Dual pathology of regional metastasis with simultaneous occurrence of tuberculous lymphadenopathy is rather rare. Herein the authors present a case of primary occult carcinoma and tuberculous lymphadenopathy in an unfortunate patient. The reliability of fine-needle aspiration cytology as a first-line investigation, with alternative methods in approaching cervical lymphadenopathy, was further dissected. [ABSTRACT FROM AUTHOR]

Solitary extrahepatic hepatocellular carcinoma without a primary lesion in the liver is rare and unique. In such patients, in addition to hepatocellular carcinoma, hepatoid adenocarcinoma, hepatoid teratoma, and hepatoid yolk sac tumor must be considered as differential diagnoses, and patients must be investigated in detail by histopathological studies with immunohistochemistry, especially using epithelial markers for which tumor cells are generally negative in hepatocellular carcinoma. A case with a solitary neoplasm of the vertebrae, which was diagnosed histopathologically as hepatocellular carcinoma, without a primary lesion is presented. The primary lesion was not identified even on autopsy, and the liver was pathologically almost normal. Given the review of the literature and circumstantial evidence, we would like to propose a bold new hypothesis that hepatocellular carcinoma might primarily originate from bone marrow. [ABSTRACT FROM AUTHOR]

Abstract Background The abscopal effect is a phenomenon in which a tumor located far from irradiated lesions regresses. We have experienced a case in which both intracranial and extracranial lesions showed an abscopal effect after radiotherapy for spinal metastases of unknown primary. We report the differential abscopal effect in extracranial and intracranial lesions. Case presentation A 57-year-old Japanese man was diagnosed with multiple lung nodules, bone metastases, and brain metastases. The results of pathological examination at the previous hospital he visited suggested adenocarcinoma of the lung. However, there was a possibility that the biopsy specimen was inadequate. Radiation therapy was performed on the ninth thoracic vertebra for a total dose of 39 Gy in 13 fractions because the lesion in the ninth thoracic vertebra was destructively extending. After thorough examination, the primary lesion could not be identified, and we made diagnosis of cancer of unknown primary. The patient did not want to receive systemic chemotherapy; however, all of the lesions except for the brain metastases had spontaneously shrunk 2 months after radiation therapy. Although the brain metastases had partially shrunk, whole-brain radiotherapy for a total dose of 36 Gy in 12 fractions was performed. Fifteen months after initial radiation therapy, the brain metastasis recurred, and Gamma Knife radiosurgery was additionally performed. The brain metastases disappeared after the radiosurgery. During a period of 30 months after radiation therapy for the ninth vertebra, the lesions of the trunk all maintained their shrinkage without systemic chemotherapy. Right cervical lymph node metastasis and brain metastases occurred 30 months after the initial radiation therapy. A biopsy of the right cervical lymph node led to the diagnosis of clear cell carcinoma. Although we considered additional radiation therapy or chemotherapy, the patient died 3 months after the progression of recurrence lesions. Discussion and conclusions We report a rare case in which radiotherapy alone for an extracranial metastatic lesion of a vertebra resulted in an abscopal effect on both extracranial and intracranial lesions. Notably, the abscopal effect in the intracranial lesions was weaker than that in the extracranial lesions.

Simple Summary: Merkel cell carcinoma is a very rare and highly aggressive neuroendocrine carcinoma originating from the skin. Exceptionally it presents with a nodal localization without a cutaneous primary site and distant metastases. This entity is controversial in terms of origin and clinical management. The main histological differential diagnosis is that of small cell neuroendocrine carcinoma. As a referral center for neuroendocrine neoplasms with more than 20 years of experience we have dealt with patients showing this clinical context several times and we usually manage them within our dedicated multidisciplinary team. Due to the extreme rarity of the entity and undefined clinical management, we report our single-center series and detail some of the diagnostic and therapeutic aspects. Our analysis can be helpful for centers which manage these patients and future investigations on the topic. Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0–68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8–79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5–95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0–97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data. [ABSTRACT FROM AUTHOR]