[Indications and early experience with transoral robotic surgery]. / Transzorális robotsebészeti beavatkozások indikációi és eddigi tapasztalataink.

Recently, organ preservation has gained importance for head and neck malignancies. The negative consequences of the therapies can be reduced without compromising the survival and the quality of life. Accordingly, transoral robotic surgery (TORS) is gaining ground internationally. We have been performing TORS procedures at the University of Pécs since January 2023. We operated on 27 patients until July 2024, including fifteen p16-positive tumors. Neck dissections were performed in 19 cases. The use of TORS is helpful in oropharyngeal cases, where inaccessible structures can be reached minimally invasively, compared to other transoral approaches. This is important for young patients with human papillomavirus-associated tumors, which have a better prognosis and longer life expectancy. TORS also has advantages over the previously used approaches for cancer of unknown primary (CUP). Compared to the standardly used FDG-PET/CT and "blindly" taken biopsies, TORS offers a higher detection rate of the primary tumor, by performing tonsillectomy and complete mucosectomy of the tongue base.

Transoral robotic surgery in the diagnosis and treatment of primary unknown head and neck squamous cell carcinoma: A preliminary single centre experience.

BACKGROUND: Squamous cell carcinoma of unknown primary (CUP) in the head and neck is difficult to diagnose and treat. This report outlines 11 cases of CUP treated with transoral robotic surgery (TORS), aimed at investigating the diagnostic efficiency of primary tumour and radical resection effectiveness of TORS. METHODS: 11 cases of CUP among 68 oropharyngeal cancer patients treated by TORS were analysed retrospectively. RESULTS: All the 11 cases received TORS with cervical lymph node dissection. Primary tumours were found in 8 cases (72.7%), 4 cases in the palatine tonsil and 4 cases in the base of the tongue. The average diameter of the primary tumour was 1.65 cm. All patients resumed eating by mouth within 24 h, no tracheotomy, no pharyngeal fistula and no postoperative death. The 3-year disease-free survival rate was 91%. CONCLUSIONS: TORS can improve the diagnostic efficiency of primary tumour of CUP and achieve good oncology and functional results.

Primary Tumour Detection in Carcinoma of Unknown Primary with Transoral Robotic Surgery (TORS) Tongue Base Mucosectomy: A Meta-analysis.

BACKGROUND: Head and neck carcinoma of unknown primary (CUP) represents a challenging diagnostic process when standard work-up fails to identify the primary tumour site. The aim of this systematic review and meta-analysis was to evaluate the diagnostic utility and complication profile of transoral robotic surgery (TORS) tongue base mucosectomy (TBM) in the management of CUP. PATIENTS AND METHODS: An electronic database search was performed in the EMBASE, MEDLINE, PubMed and Cochrane databases. A meta-analysis of proportions was performed to obtain an estimate of the overall proportion for the detection and complication rates. RESULTS: Nine studies representing 235 patients with CUP who had TORS TBM were included in the final analysis. The overall pooled tumour detection rate was 66.2% [95% confidence interval (CI) 56.1-75.8]. The incidence of tumour detection in human papilloma virus (HPV)-positive cases (81.5%, 95% CI 60.8-96.4) was significantly higher than HPV-negative cases (2.3%, 95% CI 0.00-45.7). Weighted overall complication rate was 11.4% (95% CI 7.2-16.2). The majority were grade I or II (80%) according to the Clavien-Dindo classification. CONCLUSIONS: This meta-analysis suggests TORS to be safe and effective in localising the primary tumour site in patients with CUP. While the current data supports the use of TORS in patients who are HPV positive, larger numbers of HPV-negative cases are required to determine the true diagnostic effect with TORS before any valid conclusions can be inferred in this particular subgroup. Further research should focus on high quality prospective trials with stringent methodological work-up to minimise heterogeneity and allow for more accurate statistical analysis.

Neuroendocrine Tumors of Unknown Primary in the Setting of Cytoreductive Hepatectomy.

BACKGROUND: Surgical cytoreduction for neuroendocrine tumor liver metastasis (NETLM) consistently shows positive long-term outcomes. Despite reservations in guidelines for surgery when the primary tumor is unidentified (UP-NET), this study compared the surgical and oncologic long-term outcomes between patients with these rare cases undergoing cytoreductive surgery and patients who had liver resection for known primaries. METHODS: The study identified 32 unknown primary liver metastases (UP-NETLM) in 522 retrospectively evaluated patients who underwent resection of well-differentiated NETLM between January 2000 and December 2020. Tumor and patient characteristics were compared with those in 490 cases of liver metastasis from small intestinal (SI-NETLM) or pancreatic (pNETLM) primaries. Survival analysis was performed to highlight long-term outcome differences. Surgical outcomes were compared between liver resections alone and simultaneous primary resections to assess surgical risk distinctions. RESULTS: The UP-NET patients had fewer NETLMs (p = 0.004), which on the average were larger than SI-NETLMs or pNETLMs (p = 0.002). Expression of Ki-67 was balanced among the groups. Major hepatectomy was performed more often in the UP-NETLM group (p = 0.017). The 10-year survival rate of 53% for UP-NETLM was comparable with that for SI-NETML (58%; p = 0.463) and pNETLMs (47%; p = 0.497). The median hepatic progression-free survival was 26 months for the UP-NETLM patients and 25 months for the SI-NETLM patients compared to 12 months for the pNETLM patients (p < 0.001). Perioperative mortality was lower than 2%, and severe postoperative morbidity occurred in 21%, similarly distributed among all the groups. CONCLUSION: The surgical risk and long-term outcomes for the UP-NETLM patients were comparable with those for other NETLM cases, affirming the validity of equally aggressive surgical cytoreduction as a therapeutic option in carefully selected cases.

[A Patient with Cancer of Unknown Primary Who Responded to Chemotherapy].

Cancer of unknown primary is a class of malignant tumors, histologically identified as metastatic lesions whose primary origin is unknown despite adequate investigations for the primary tumor. Although the prognosis of cancer of unknown primary is generally poor, here, we report our experience with a patient who responded to chemotherapy. The patient was a 78-year-old woman. She had a history of gastric cancer at the age of 76 years. In June of year X-1, she was diagnosed with gastric cancer(tub1>tub2, pT1bN0M0, pStage Ⅰa)and underwent distal gastrectomy. One year after surgery, computed tomography revealed right supraclavicular lymphadenopathy, for which cervical lymphadenectomy was performed. The pathological diagnosis was ductal carcinoma with comedo necrosis and poorly differentiated solid adenocarcinoma that were suggestive of metastases from breast cancer. However, a detailed examination of the mammary glands revealed no mass. Imaging studies led to a diagnosis of cancer of unknown primary. Therefore, chemotherapy, according to the treatment of pancreatic cancer, was planned based on immunostaining, tumor markers, etc. Chemotherapy response evaluation after completing 4 courses demonstrated a partial response; the patient responded to the chemotherapy. We considered that estimating primary lesions from histopathological images, tumor markers, etc., may help determine effective chemotherapy regimens.

Inguinal nodal metastatic squamous cell carcinoma of unknown primary (CUP) detected 7 years before the diagnosis of vulvar squamous cell carcinoma: A case report.

OBJECTIVE: Metastatic squamous cell carcinoma (SCC) of inguinal lymph node region with unknown origin is a rare condition. A patient was diagnosed to have vulvar SCC 7 years after the initial diagnosis of inguinal nodal metastatic SCC of unknown primary. CASE REPORT: A 59-year-old woman with metastatic SCC of unknown origin in the right inguinal lymph node underwent tumor resection and no evidence of residual disease or possible tumor origin was detected after the surgery and a comprehensive work-up. Seven years later, she was diagnosed to have invasive right vulvar SCC with right pelvic lymph node metastasis. We performed a series of tests to evaluate the relationship between these two events. CONCLUSION: According to our investigation, the possible relationship between the two events could not be ruled out. This case emphasizes the possibility of late recurrence and the importance of long-term follow up for patients with isolated nodal CUP.

Transoral robotic tongue base mucosectomy for head and neck cancer of unknown primary: six-year outcome experience.

BACKGROUND AND OBJECTIVE: Head and neck carcinoma of unknown primary is a diagnostic dilemma. The clinical and imaging workup remains ineffective in two-thirds of patients. Transoral robotic surgery has shown an advantage in the primary detection over the previous standard panendoscopy. METHODS: This is an observational cohort study that took place at a large healthcare centre with robotic surgery experience in head and neck over six-years. All included carcinoma of unknown primary patients followed the standard recommendation for primary identification. Final diagnostic step of robotic tongue base mucosectomy with or without tonsillectomy was introduced. The cancer detection rate in tongue base only, the functional outcome and the effect on the cancer pathway were evaluated. RESULTS: Carcinoma of unknown primary was reported in 44 per cent of patients. All identified specimens were human papillomavirus positive. There was no significant effect on functional outcome of swallowing and the national 62-day cancer pathway. Robotic surgery allowed optimum treatment of carcinoma of unknown primary in early nodal disease. CONCLUSION: Robotic surgery is a useful paradigm in the management of carcinoma of unknown primary. It is safe with minimal morbidity and good functional outcome after the surgery.

Step Serial Sectioning in Head and Neck Squamous Cell Carcinoma of Unknown Primary.

Importance: Patients with suspected head and neck squamous cell carcinoma of unknown primary (HNSCCUP) may undergo tonsillectomy and tongue base mucosectomy (TBM) to help identify clinicoradiologically occult primary disease. It is hypothesized that when these diagnostic specimens are analyzed, conventional histopathological (CH) techniques risk missing small primary tumors that may be hidden in the tissue blocks. Objective: To establish the outcomes of a step serial sectioning (SSS) histopathological technique vs CH when analyzing diagnostic tissue specimens from TBM and tonsillectomy performed for HNSCCUP. Design, Setting, and Participants: The MOSES prospective multicenter noninterventional cohort study was conducted over a 25-month period from November 2019 at secondary and tertiary care ear, nose, and throat departments in the United Kingdom and included adults with clinicoradiologically occult HNSCCUP who were undergoing TBM. Intervention: Conventional histopathological techniques performed on TBM and tonsillectomy specimens at participating centers, followed by SSS performed at the central laboratory. Main Outcome: Identification of cancer on central histopathological review of TBM and tonsillectomy specimens. Results: Tissue from 58 eligible patients was analyzed (median [range] age, 58 [47-82] years; 10 women [17%]), with 20 480 sections cut in the laboratory and 4096 sections directly examined by a pathologist (median [range], 64 [28-135] per patient). The overall identification rate for TBM following SSS according to study protocol was 50.0% (95% CI, 37.5%-62.5%) and by subgroups was 42.9% (95% CI, 21.4%-67.4%) when performed following a negative bilateral tonsillectomy, 46.7% (95% CI, 24.8%-69.9%) at the same time as bilateral tonsillectomy, and 57.1% (95% CI, 36.5%-75.5%) following historic tonsillectomy. Conventional histopathological techniques at central review identified 2 undiagnosed primary tumors and revised the diagnosis of 2 other cases (1 nonmalignant and another down staged). Step serial sectioning identified a single additional tumor: an ipsilateral synchronous tongue base tumor for which a contralateral tumor had been identified on CH. Multifocal disease was seen in 5 (8.6%); all were human papillomavirus-related and in the tongue base. Conclusions and Relevance: In this multicenter cohort study of patients undergoing TBM for HNSCCUP, SSS was associated with added considerable histopathological workload with minimal additional diagnostic benefit. A second opinion for conventional histological techniques may be more beneficial. Synchronous primary disease should be considered when planning diagnostic oropharyngeal surgery for these patients.

Transoral robotic surgery in HPV+ oropharyngeal cancer of unknown primary.

PURPOSE: This study was designed to assess trends in and outcomes associated with TORS-treated HNCUP using a large national database. MATERIALS AND METHODS: HPV+ oropharyngeal HNCUPs were isolated from the 2004-2017 National Cancer Database. Overall survival (OS) was assessed, with patients stratified by 1) use of TORS and 2) whether the occult tumor was ultimately located. Demographic and oncologic predictors of survival were evaluated on regression. RESULTS: The cohort contained 284,734 cases, of which 8336 were HNCUPs. HNCUPs represented 2.49 % of all HNSCC in 2010 versus 3.13 % in 2017. 3897 (46.7 %) of these unknown primaries were ultimately identified. The proportion of cases treated with TORS increased from 6.9 % in 2010 to 18.1 % in 2017 (p < 0.001). Kaplan-Meier analysis of 2991 HPV+ oropharyngeal HNCUPs demonstrated higher 5-year overall survival (OS) for patients treated with robotic surgery versus no robotic surgery (95.4 % ± 1.7 % standard error [SE] versus 84.0 % ± 0.9 % SE; p < 0.001). Patients with primary tumors identified during treatment had improved OS compared to those whose tumors were not located (5-year OS was 90.5 % ± 0.9 % SE and 77.3 % ± 1.5 % SE, respectively; p < 0.001). For patients in which the primary tumor was found, those who received robotic surgery survived longer than those who did not (96.5 % ± 1.4 % SE versus 89.1 % ± 1.0 % SE 5-year OS; p < 0.001). The relationship between TORS and OS remained significant on Cox regression controlling for confounders. CONCLUSIONS: Use of TORS in the workup for HPV+ HNCUP is associated with higher rates of tumor identification and improved OS.

A Look at the Other Side: High-Risk Lesions and Occult Contralateral Malignancy in Symmetry Procedures for Patients Undergoing Oncoplastic Breast-Conserving Surgery.

BACKGROUND: The incidence of occult breast cancer among patients undergoing reduction mammoplasty or risk-reducing mastectomies ranges from 1% to approximately 10%, respectively. Identification of incidental cancer often mandates subsequent mastectomy due to ambiguous margins. This study aimed to determine the incidence of contralateral malignancy among patients undergoing oncoplastic breast-conserving surgery (OBCS) with concurrent symmetry procedures. METHODS: The authors reviewed their prospectively maintained institutional database of patients with unilateral breast cancer who underwent OBCS. Patients who underwent excisional biopsy on the contralateral breast were analyzed separately. Patient demographics, pathologic features, and subsequent disease management were evaluated. RESULTS: Between March 2018 and July 2022, 289 patients underwent OBCS with a symmetry procedure, and 100 patients yielded contralateral breast tissue specimens. For 14 patients, a planned excisional biopsy was performed with their symmetry procedure, and five lesions (36%) were found to be malignant. Of the remaining 86 patients, 92% underwent preoperative breast magnetic resonance imaging (MRI). Four patients (4.7%) had occult malignancies identified on the contralateral breast pathology; three patients with ductal carcinoma in situ and one patient with invasive lobular carcinoma. Three patients had undergone preoperative MRI without suspicious findings. No patients required mastectomy for treatment of the contralateral breast cancer. CONCLUSION: The incidence of occult malignancy among OBCS symmetry procedures approaches 5%. The final pathology of excisional biopsies had a higher upgrade rate than previously reported. All identified malignancies were early-stage disease. The higher incidence of occult breast cancer in this population warrants the routine orientation of all specimens, which allows patients with incidental early-stage cancer the option of breast preservation.

Surgical debulking is associated with improved survival for patients with neuroendocrine liver metastases of unknown primary.

BACKGROUND: Resection of neuroendocrine tumors (NET) with surgical debulking of liver metastasis (NETLM) is associated with improved survival. In patients with an unknown primary (UP-NETLM), the effects of debulking remains unclear. METHODS: The National Cancer Database (2004-2016) was queried for patients with small intestine (SI) and pancreas (P) NETLMs. If the liver was listed as the primary site, the patient's disease was classified as UP-NETLM. RESULTS: Patients with UP-NETLM, SI-NETLM, and P-NETLM who were managed non-operatively demonstrated a significant difference in 5-year overall survival (OS) (21.5% vs. 39.2% vs. 17.1%; p < 0.0001). OS in patients who underwent debulking was higher (63.7% vs. 73.2% vs. 54.2%). Patients with UP-NETLMs who underwent debulking had similar OS to patient with SI-NETLM (p = 0.051), but significantly higher OS, depending on tumor differentiation, compared to patients with P-NETLMs. If well-differentiated, surgery for UP-NETLMs was associated with a higher rate of OS (p = 0.009), while no difference was observed if moderately (p = 0.209) or poorly/undifferentiated (p = 0.633). P-NETLMs were associated with worse OS (p < 0.001) on multivariate analysis. DISCUSSION: Debulking in patients with UP-NETLMs was associated with similar OS compared to patients with SI-NETLMs and better or similar OS compared to patient with P-NETLMs.

Portsite metastasis of adenocarcinoma after laparoscopic cholecystectomy with an unknown primary tumor: a case report.

Port site metastasis of adenocarcinoma after laparoscopic cholecystectomy with an unknown primary tumor is rare. To the best of our knowledge, there are only four such cases reported worldwide. We report a woman in her 70s with cholecystitis who underwent laparoscopic cholecystectomy. Intraoperative laparoscopic exploration did not reveal an abdominal tumor, and postoperative gallbladder pathology did not suggest malignancy. However, 11 months later, she developed an incisional mass in the epigastric port site. In another 6 months, magnetic resonance imaging revealed an abdominal wall tumor. Therefore, she underwent radical resection of the subcutaneous tumor, and postoperative pathology revealed adenocarcinoma. However, no primary tumor was found after systemic imaging examination.

Clinical characteristics and outcomes of cervical lymph node metastasis from unknown primary sites: a single institution's 14-year experience.

BACKGROUND: Cervical lymph node metastasis from unknown primary sites is a challenging clinical issue with a changing therapy model and unpredictable outcomes, which leads to the difficulty in selecting optimal treatments. Thus, it is valuable to analyze the clinical characteristics and outcomes of the patients who receive different management styles. METHODS: All patients with cervical lymph node metastasis from unknown primary sites were reviewed and no primary lesions were found. In addition, this work was funded by the Clinical Trial Fund Project of Tianjin Medical University Cancer Institute and Hospital (No. C1716). Specifically, we used univariate, multiple regression analysis to evaluate the factors associated with prognosis. RESULTS: 365 patients met the inclusion criteria, and the 2- and 5-year survival rates were 77.0% and 33.4%, respectively, with a median survival of 45 months. Gender, age, pathological type, nodal status, and necessary cervical lymph node dissection affected locoregional control. Distant metastasis was common in individuals with a pathological type of adenocarcinoma, poor differentiation, and advanced nodal status. Furthermore, patients who received induction chemotherapy had a better prognosis than those treated with postoperative chemotherapy. Multiple regression analysis showed that pathological grade, treatment models, and distant metastasis were associated with overall survival (OS) and progression-free survival (PFS). In addition, local recurrence exerted a significant influence on OS. Induction chemotherapy and postsurgical radiotherapy seemed to improve the prognosis of patients at the advanced stage compared with simple surgery and postsurgical chemotherapy. CONCLUSIONS: Pathological grade, treatment models, and distant metastasis were independent risk factors for prognosis. Induction chemotherapy or postoperative radiotherapy benefited patients at the advanced stage, and patients with adenocarcinoma, poor differentiation, and advanced nodal status should undergo induction chemotherapy in light of the increased risk of distant metastasis.

Survival after lymphadenectomy of nodal metastases from melanoma of unknown primary site.

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.

Prophylactic mastectomy and occult malignancy: Surgical and imaging considerations.

BACKGROUND: Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations. METHODS: All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM. RESULTS: The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM. CONCLUSIONS: Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered.

Laser tongue base mucosectomy is a useful diagnostic tool in the management of unknown primary cancers of the head and neck region.

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.

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

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

Microsatellite Instability-high-positive Cancer of Unknown Primary Origin with a Long-term Survival after Surgery Alone.

An 80-year-old woman was referred to our hospital for a thorough examination of enlarged lymph nodes on the lesser curvature of the stomach. Upon suspicion of malignant lymphoma, the patient underwent open lymphadenectomy and was diagnosed with lymph node metastasis of poorly differentiated adenocarcinoma. The patient was subsequently diagnosed with microsatellite instability-high cancer of unknown primary origin. Surgical removal of the affected lymph nodes achieved full remission. Chemotherapy was considered in case of recurrence or identification of the primary site. Recurrence has not occurred in three years since the surgery. However, a long-term survival without chemotherapy is rare.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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%. CONCLUSIONS: FLIm may be a useful diagnostic adjunct for detecting HNSCCUP.