Carcinoma Of Unknown Primary Origin Research Articles

Utility of UV Signature Mutations in the Diagnostic Assessment of Metastatic Head and Neck Carcinomas of Unknown Primary.

Metastatic carcinoma of unknown primary origin to the head and neck lymph nodes (HNCUP) engenders unique diagnostic considerations. In many cases, the detection of a high-risk human papillomavirus (HR-HPV) unearths an occult oropharyngeal squamous cell carcinoma (SCC). In metastatic HR-HPV-independent carcinomas, other primary sites should be considered, including cutaneous malignancies that can mimic HR-HPV-associated SCC. In this context, ultraviolet (UV) signature mutations, defined as ≥ 60% C→T substitutions with ≥ 5% CC→TT substitutions at dipyrimidine sites, identified in tumors arising on sun exposed areas, are an attractive and underused tool in the setting of metastatic HNCUP. A retrospective review of institutional records focused on cases of HR-HPV negative HNCUP was conducted. All cases were subjected to next generation sequencing analysis to assess UV signature mutations. We identified 14HR-HPV negative metastatic HNCUP to either the cervical or parotid gland lymph nodes, of which, 11 (11/14, 79%) had UV signature mutations, including 4 (4/10, 40%) p16 positive cases. All UV signature mutation positive cases had at least one significant TP53 mutation and greater than 20 unique gene mutations. The management of metastatic cutaneous carcinomas significantly differs from other HNCUP especially metastatic HR-HPV-associated SCC; therefore, the observation of a high percentage of C→T with CC →TT substitutions should be routinely incorporated in next generation sequencing reports of HNCUP. UV mutational signatures testing is a robust diagnostic tool that can be utilized in daily clinical practice.

Clinicopathological features, psychological status, and prognosis of 33 patients with occult breast cancer.

Occult breast cancer (OBC) has traditionally been considered to be a carcinoma of unknown primary origin with a favorable prognosis and can be treated as stage II-III breast cancer. Due to the small number of cases and limited clinical ex-perience, treatments vary greatly around the world and no standardized treat-ment has yet been established. To investigate the clinicopathological features, psychological status and prog-nostic features of patients with OBC. The clinicopathological data of 33 OBC patients diagnosed and treated in the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital from November 2015 to November 2022 were retrospectively analyzed. The psychological status of OBC patients was evaluated by the Self-rating Anxiety Scale and Self-rating Depression Scale. Patients' emotions, stress perception and psychological resilience were evaluated by the Positive and Negative Affect Schedule, the Chinese Perceived Stress Scale, and the Connor-Davidson Resilience Scale (CD-RISC), respectively. Patient survival was calculated using the Kaplan-Meier method, and survival curves were plotted for analysis with the log-rank test. Univariate and multivariate survival analyses were performed using the Cox regression model. The 33 OBC patients included 32 females and 1 male. Of the 33 patients, 30 (91%) had axillary tumors, 3 (9%) had a neck mass as the primary symptom; 18 (54.5%) had estrogen receptor-positive tumors, 17 (51.5%) had progesterone receptor-positive tumors, and 18 (54.5%) had Her-2-positive tumors; 24 (72.7%) received surgical treatment, including 18 patients who underwent modified radical mastectomy, 1 patient who underwent breast-conserving surgery plus axillary lymph node dissection (ALND), and 5 patients who underwent ALND alone; 12 patients received preoperative neoadjuvant therapy. All 30 patients developed anxiety and depression, with low positive affect scores and high negative affect scores, accompanied by a high stress level and poor psychological resilience. There were no differences in the psychological status of patients according to age, body mass index, or menopausal status. The overall survival and disease-free survival (DFS) of all the patients were 83.3% and 55.7%, respectively. Univariate analysis demonstrated that the initial tumor site (P = 0.021) and node stage (P = 0.020) were factors that may affect patient prognosis. The 5-year DFS rate of OBC patients who received radiotherapy was greater (P < 0.001), while the use of different surgical methods (P = 0.687) had no statistically significant effect on patient outcomes. Multivariate analysis revealed that radiotherapy (P = 0.031) was an independent prognostic factor. Receiving radiotherapy had a significant effect on the CD-RISC score (P = 0.02). OBC is a rare breast disease whose diagnosis and treatment are currently controversial. There was no significant difference in the efficacy of other less invasive surgical procedures compared to those of modified radical mastectomy. In addition, radiotherapy can significantly improve patient outcomes. We should pay attention to the psychological state of patients while they receive antitumor therapy.

Osteoclasts in bone marrow metastases by carcinoma of unknown primary origin

Osteoclasts in bone marrow metastases by carcinoma of unknown primary origin

Osteoclasts in bone marrow metastases by carcinoma of unknown primary origin

Osteoclasts in bone marrow metastases by carcinoma of unknown primary origin

Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study

Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

Intraoperative Flow Cytometry Upon and Beyond the Cell Cycle: A Case Study of the Characterization of a Bone Metastasis

The accurate assessment of malignancy and the precise characterization of cancer type are pivotal in guiding clinical decisions and ensuring optimal patient outcomes. The challenging task of identifying the primary site of carcinoma, especially during a surgical procedure, is not always possible and necessitates the exploration of novel, innovative diagnostic techniques. In this report, we detail a unique case of carcinoma of unknown primary origin encountered during an orthopedic surgical procedure. We introduce a novel intraoperative flow cytometry (iFC) methodology, distinctly different from traditional flow cytometry, which is tailored for real-time assessment during surgeries. This iFC technique, applied in a bone metastasis case of unknown primary origin, enabled DNA content analysis and the quantification of cytokeratin for rapid malignancy characterization, presenting an avenue for immediate surgical guidance and decision making. The case was distinctively characterized using iFC, shedding light on the potential of this emerging technique. iFC has been gaining traction because of its ability to facilitate cancer cell assessment and margin evaluation. It has been successfully applied across a wide spectrum of neoplastic conditions. Our innovative, two-step approach using iFC encompasses (1) DNA content analysis, which serves as a reliable indicator for the detection of cancer cells, and (2) the quantification of cytokeratin, a pivotal marker, which aids in the characterization and classification of a malignancy. In this case, the malignancy was classified as a carcinoma. The findings obtained from iFC were subsequently validated through pathology assessment, confirming the accuracy and reliability of our approach. This noteworthy case strengthens the potential of iFC as a novel tool in malignancy assessment, which is not just limited to cell cycle analysis but instead extends beyond this application. The promising results obtained from this case study serve as a testament to the need for more extensive research in clinical studies.

Multiple Bone Metastases as the Initial Presentation of Occult Breast Carcinoma in a Kidney Transplant Recipient

Introduction: Due to their immunosuppressive medication regimen, solid organ transplant recipients have an increased risk of developing cancer, which might jeopardize their survival. Specifically, cardiovascular disease and malignancy are the two leading causes of death in kidney transplant recipients. In solid organ recipients, cutaneous malignancies, lymphomas, and Kaposi’s sarcomas also appear to be the most prevalent cancer forms. Thus, carcinoma of unknown primary origin is a clinical entity that diagnosing requires a high level of suspicion and thorough reviewing of laboratory, radiological, and clinical findings. Further, susceptible patients, such as immunocompromised ones, should merit a careful analysis of findings and detailed analytic rationale. We, therefore, present the following case report demonstrating the importance of follow-up of specific suspicious serum markers in transplant patients. To our knowledge, this study is the first case to report an occult breast carcinoma as the initial presentation in a patient with a kidney transplant.Case Presentation: In the following case, the primary indication for malignancy was elevated alkaline phosphatase (ALP), a common finding in patients with chronic renal failure. Once noticed in a scheduled post-transplantation follow-up, further diagnostic tests, such as a broader serum panel, sternal puncture, and mammography, were ordered and returned normal. Subsequently, CT was ordered and revealed lytic and sclerotic bone changes. Afterward, serum tumor markers were ordered together with gynecological ultrasound and PET-CT. Finally, an iliac bone marrow biopsy confirmed a breast cancer diagnosis of unknown primary origin, causing the elevated ALP.Conclusions: This case report presents a uniquely difficult diagnostic challenge as an expected elevated value of ALP in a kidney transplant recipient was the only diagnostic clue for occult breast carcinoma. We discuss further the vigilance that physicians must exert when dealing with kidney transplant recipients and the implication of carcinoma of unknown primary in this population.

Carcinoma of Unknown Primary Origin: Application of Immunohistochemistry With Emphasis to Different Cytokeratin 7 and 20 Staining Patterns.

Although the primary origin of some carcinomas may be obscure to clinicians, its identification is crucial as it affects prognosis and treatment (especially novel targeted therapies). Immunohistochemistry (IHC) may be helpful in identifying the primary origin of carcinomas. This retrospective survey aimed to evaluate the frequency and accuracy of each IHC marker used to determine the origin of carcinomas. The review of pathology department archives revealed 307 cases of cancer of unknown primary origin (CUP) between 2015 and 2020, which were accessible in the department archives. Demographic information, site of biopsy, clinical and pathologic diagnoses, and IHC results of the patients were collected. The patients included 157 (51.15%) men and 150 (48.85%) women. The age of the patients ranged from 14 to 92 years, including 106 (34.5%) expired cases. In 27% of cases, the primary origin of carcinoma remained unknown. The agreement between pathologic and clinical diagnoses was 59%. The most common pattern of cytokeratin (CK) expression in CUP was CK7+/CK20- (55.3%), followed by CK7-/CK20- (19%), CK7+/CK20+ (15%), and CK7-/CK20+ (10.7%), respectively. The IHC analysis may improve the diagnosis of CUPs. However, the origin of some cases remains unknown despite an IHC analysis, thereby necessitating the use of more diagnostic procedures or gene expression studies for reaching a definitive diagnosis.

Intraoperative delineation of p16+ oropharyngeal carcinoma of unknown primary origin with fluorescence lifetime imaging: Preliminary report.

This 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). FLIm 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. Among 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%. FLIm may be a useful diagnostic adjunct for detecting HNSCCUP.

Patterns of care in the radiotherapeutic management of head and neck cancer of unknown primary origin: in search of a standard

AbstractObjectiveTo analyze patterns of care in radiotherapy field design for patients treated for head and neck squamous cell carcinoma of unknown primary origin in the modern era.MethodsFrom January 2014 to April 2018, 33 patients were treated by intensity‐modulated radiation therapy for squamous cell carcinoma metastatic to the cervical lymph nodes of unknown primary origin. A total of 17 patients (52%) were treated by primary radiation; 16 (48%) were treated after surgery. N‐classification was N1 (3 patients); N2a (8 patients); N2b (15 patients); N2c (2 patients); and N3 (5 patients).  Human papillomavirus status was positive in 19 (58%) and negative in 14 patients (42%). ResultsA total of 15 patients (46%) were treated with classic comprehensive fields to the entirety of the pharyngeal mucosal axis and bilateral cervical necks. Seven patients (21%) received ipsilateral neck radiation only. The total mucosal axis was irradiated in 15 patients (46%). Among the entire population, the nasopharynx and larynx were intentionally omitted in 36% and 48%, respectively. None of the clinical parameters predicted for the use of less‐than‐comprehensive radiation fields (P &gt; 0.05, for all).ConclusionSignificant variation exists in the radiotherapeutic management of head and neck unknown primary cancer. Further research to better optimize standards is required.

A Case of Anti-Hu Antibody-positive Paraneoplastic Neurological Syndrome due to Mediastinal Lymph Node Small Cell Carcinoma of Unknown Primary Origin

A Case of Anti-Hu Antibody-positive Paraneoplastic Neurological Syndrome due to Mediastinal Lymph Node Small Cell Carcinoma of Unknown Primary Origin

The Role of Immunohistochemistry in the Workup of Malignant Neoplasms of Unknown Primary Origin at Khartoum Oncology Hospital

Background: Carcinoma of unknown primary origin (CUP) comprises various malignancies classified by detection of tissue-specific genes through immunohistochemistry (IHC). We aimed to explore the role of available immunohistochemical markers in diagnosing and classifying malignant neoplasms of unknown primary origin.Methods: A cross-sectional study included 141 patients diagnosed histologically as CUP and referred to the Histopathology and Immunohistochemistry Department, Khartoum Oncology Hospital, from 2012 to 2017. Hematoxylin and Eosin (H&amp;E) and immune stained slides used in the workup were reviewed and classified into the main histologic types of CUP. Data were -analyzed by SPSS. Results: Out of 4436 cases, CUP represents (3.2%). The age group (60-69) years have the highest percentage (20.13%), with male predominance (51.77%). Lymph nodes represent (41.84%) followed by the liver (12.77%), spine (3.55%), and lungs (2.13%). Adenocarcinoma (75.89%) was the most common subtype, followed by undifferentiated neoplasm (14.18%), squamous cell carcinoma (7.09%), and carcinoma with neuroendocrine differentiation (2.84%). In 70 cases (49.6%) of the study cases, the primary site was determined, (17.7%) were given an only differential diagnosis, and in (32.6%) the origin remains unknown. Conclusions: CUP cases during the study period are infrequent (3.2%), and the primary origin was determined in nearly half of patients by the available immune markers. CUP’s common histological types were adenocarcinoma, undifferentiated neoplasm, squamous cell carcinoma, and carcinoma with neuroendocrine differentiation. The most common presenting sites were lymph node, liver, spine, and lungs.

1804P Baseline mutational profiles of patients (pts) with carcinoma-of-unknown-primary-origin (CUP) enrolled onto CUPISCO

NCCN guidelines consider next-generation sequencing important in guiding therapeutic decision-making in CUP. CUPISCO (NCT03498521) is an ongoing, phase II randomised study of targeted therapy/cancer immunotherapy vs platinum-based chemotherapy in pts with unfavourable CUP, defined per ESMO guidelines. We present a preliminary, descriptive molecular analysis of ∼50% of pts designated for enrolment.

The clinicopathological characteristics, gene mutation characteristics and survival analysis of carcinoma of unknown primary origin.

e15098 Background: Analyze the characteristics of CUPS clinicopathology and gene mutation spectrum, and discuss CUPS drug treatment strategies. Methods: A retrospective analysis of the data of 30 patients with metastatic cancer of CUP admitted to our department from April 2015 to April 2020. Including clinicopathological characteristics, treatment process and methods, gene molecular information, follow-up survival period. The follow-up was until February 1, 2021 or the patient died. Results: The pathological types of these cases were adenocarcinoma (14/30,46.7%), squamous cell carcinoma (5/30, 16.7%), neuroendocrine carcinoma (3/30,10%), small cell carcinoma (2/30,6.7%), sarcomatoid carcinoma (2/30,6.7%), large cell carcinoma (1/30,3.3%), lymphoepithelial carcinoma (1/30,3.3%), and poorly differentiated carcinoma (2/30,6.7%) . The most predilection site was lymph nodes, accounting for 70%. Primary lesions were not found in 23 cases in the course of diagnosis and treatment. They were head and neck in 1 case, lung in 1 case, mammary gland in 1 case, digestive tract in 3 cases and thymus in 1 case. 23 patients received chemotherapy alone or combined with antiangiogenic therapy, 2 patients received molecular targeted agents, 1 patient received ICI combined with antiangiogenic therapy, and the remaining 4 patients died without antitumor therapy or gave up treatment. The survival time of 26 patients was between 1 to 143 months, and the median survival time was 8.6 months. The 1-year, 2-year, 3-year and 5-year OS rate were 40%, 20%, 6.7% and 3.3%, respectively. Mean survival time was significantly longer among patients without visceral metastasis vs. with visceral metastasis (15.6m vs. 7.3m, P = 0.023). OS rate were 70% vs. 25%, 30% vs. 15%, 20% vs. 0% and 10% vs. 0%, respectively. The median survival time were 18.3m (with targeted therapy), 8.8m (without targeted therapy), 23.2m (with primary lesion), 8.4m (without primary lesion), The 1-year, 2-year, 3-year and 5-year OS were 53.3% vs. 26.7%, 40% vs. 0%, 23.3% vs. 0% and 6.7% vs. 0% for patients with targeted therapy vs. without targeted therapy, respectively. The 1-year, 2-year, 3-year and 5-year OS were 85.7% vs. 261%, 42.9% vs. 13%, 28.6% vs. 0% and 14.3% vs. 0% for patients with primary lesion vs. without primary lesion, respectively. 20 patients were interrogated genes using NGS of ctDNA. 80% of patients exhibited ctDNA alterations; TP53-associated genes were most commonly altered (13/20,65%) followed by genes involved in the MAPK pathway (20%), PI3K signaling (10%) and the cell cycle machinery (5%). The genomic profiles help guide treatment in 4 cases. Conclusions: CUPS has a poor prognosis. The pathological type is mostly adenocarcinoma, and lymph node metastasis is the first diagnosis. Chemotherapy is still the main treatment method. Molecular detection is helpful for individualized treatment.

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors

Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. To determine which patients derived the greatest degree of clinical benefit from NGS profiling. Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

A Challenging Surgical and Reconstructive Approach to Locally Advanced Squamous Perineal Carcinoma: A Case Report and Literature Review

Perineal carcinoma of unknown primary origin (CUP) is a rare entity and represents a diagnostic and therapeutic challenge. These tumors may respond well to a combination of surgical resection, when feasible, local radiotherapy, and platinum-based systemic chemotherapy. A 67-year-old male patient consulted for urinary discomfort associated with perineal abscess. The perineal abscess was drained, and the patient was diagnosed with perineal carcinoma of unknown origin. Computed tomography (CT) scan shows a large perineal mass that involves both corpora cavernosa and corpus spongiosum. CT and bone scan excluded the metastatic spread of the disease. Inguinal lymph nodes were not identified. The surgical treatment consisted of two different phases. Phase I: the perineal mass exeresis with total penectomy. Phase II: perineal neourethrostomy with double oral mucosa graft. Coverage of the perineal defect and morphological reconstruction of the penis with fasciocutaneous and gracilis flap. The surgical intervention lasted for nine hours and the estimated blood loss was 500cc. The patient was discharged twelve days after the intervention. Later he received adjuvant treatment with immunotherapy (Cemiplimab) because was not subsidiary to treatment with platinum for renal failure. The patient died after nine months of follow-up due to pulmonary and abdominal metastatic spread.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design.

BackgroundCarcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.Materials and MethodsCentrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined.ResultsA total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.ConclusionsThirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521Implications for PracticeThe findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment.

Application of the Roche Cobas® HPV 4800 in Formalin-Fixed, Paraffin-Embedded Samples for Head and Neck Squamous Cell Carcinomas.

Testing for high risk human papillomavirus (HR-HPV) status is standard of care in squamous cell carcinomas of the oropharynx as well as cervical lymph node squamous cell carcinomas of unknown primary origin. DNA or RNA in-situ hybridization (ISH) and p16 immunohistochemistry, widely used currently for HPV detection are operator-dependent. In addition, DNA ISH has a relatively low sensitivity, and p16 is not entirely specific for HR-HPV infection. In this study, we examined the performance of the cobas® HPV genotyping assay in formalin-fixed, paraffin-embedded (FFPE) samples of head and neck squamous cell carcinoma. FFPE samples from head neck and other anatomic sites tested by ISH and p16 for HR-HPV at ARUP Laboratories were selected for this study. Samples were deparaffinized, stained and micro-dissected for tumor contents followed by tissue lysis, then tested with cobas® for HR-HPV. All the samples were also tested by HPV Linear Array for confirmation. All (N = 18) high risk HPV positive specimens tested by cobas® were confirmed as positive by the Linear Array test. All the specimens tested as negative by cobas® were tested as negative (N = 5) or positive only for low risk HPV (N = 3) by Linear Array, as cobas® only detects HR HPV. Limits of detection for HPV16 and 18 were established at 160-320 and 320-1600 copies, respectively. Our data suggest that cobas® HR-HPV genotyping is a viable option for detection of HR-HPV in formalin-fixed, paraffin-embedded samples from head and neck and other anatomic sites and has been validated for clinical use.

SMARCB1-deficient carcinomas of the head and neck region: a cytopathologic characterization

SMARCB1 encodes for a component of the SWI/SNF complex and is widely implicated in carcinogenesis. In the head and neck, SMARCB1-deficient carcinomas typically arise in the sinonasal tract but can be found at other sites. EZH2 inhibitors have emerged as potential targeted therapy against SWI/SNF-deficient tumors. We sought to characterize the cytomorphology of head and neck carcinomas with SMARCB1 deficiencies to identify potential candidates for targeted therapy. Head and neck carcinomas with SMARCB1 mutations were retrospectively identified and confirmed to be SMARCB1-deficient by both molecular (fluorescent in-situ hybridization or next generation sequencing) and immunohistochemical means. Cases with positive cytology were reviewed and their cytologic features cataloged. A total of 19 specimens from 13 patients were reviewed, including 8 specimens from 7 sinonasal carcinomas, 4 specimens from 3 thyroid carcinomas, 3 specimens from 2 skin carcinomas, and 4 specimens from 1 carcinoma of unknown primary origin. High-grade features were common, including mitoses (11 of 19) necrosis (13 of 19) and multinucleation (16 of 19). Tumors showed either dense cytoplasm with distinct cell borders (10 of 19) or delicate cytoplasm with indistinct cell borders (9 of 19). Most tumors showed no distinct epithelial differentiation (12 of 19), while some (7 of 19) showed glandular or signet ring features. A minor cohort demonstrated rhabdoid cells (4 of 19). Head and neck carcinomas with SMARCB1 deficiencies have a wide array of morphologies and tend to demonstrate high-grade features. Only a minor cohort demonstrate rhabdoid-type cells. Evaluation of SMARCB1 deficiency for potential targeted therapy should not be limited to tumors with rhabdoid morphology.

Detection and Oncologic Outcomes of Head and Neck Squamous Cell Carcinoma of Unknown Primary Origin.

To assess factors that predict detection of tumors and oncologic outcomes in head and neck squamous cell carcinoma of unknown primary (SCCUP). This was a retrospective cohort study at a single tertiary care institution. The primary site was detected at examination under anesthesia (EUA) in 92 (51.1%) patients. The primary site was detected by directed biopsies in 60 (65%), palatine tonsillectomy in 28 (30.4%), and lingual tonsillectomy in 4 patients (4.3%). Four of eight lingual tonsillectomies were positive (50%). Primary locations included: palatine tonsils (51, 28.3%), base of tongue (37, 20.6%), larynx (4, 2.2%), oral cavity (3, 1.67%) and nasopharynx (1, 0.6%). Human papillomavirus (HPV) positive status (HR=0.26, p=0.004) and treatment with chemoradiation (CRT) (HR=0.38, p=0.004) were associated with better disease free survival (DFS). A primary site was located after aggressive investigation in approximately half of the patients. More research is warranted towards the use of lingual tonsillectomy. Predictors of favorable prognosis included HPV positive status and treatment with CRT.