Indications for oropharyngeal biopsy in head and neck squamous cell carcinoma of unknown primary: A systematic review (HNSCCUP).

INTRODUCTION: Patients presenting with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remain challenging clinical scenarios as large variation exists in practices used to locate the primary. OBJECTIVE: The objective of this systematic review is to review of the literature and offer recommendations for oropharyngeal biopsies in HNSCCUP. METHOD: Pubmed, Medline and Embase were searched to identify studies from inception to October 2021. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. RESULTS: A total of 483 articles were included and screened, 41 studies met the inclusion criteria, including over 3400 patients from the original articles (122 of these patients were reported on in two sequential articles by a single author - table 1) and 4 large metaanalyses including 1852 patients. The primary site identification rate following random biopsies or deep tissue biopsies is less than 5% in most studies. The mean detection rate following ipsilateral tonsillectomy is 34%; two pooled analyses indicate that the mean detection rate following tongue base mucosectomy is 64%, with this figure rising when the tonsils are negative. CONCLUSIONS: High level evidence is lacking, with heterogeneity in the reported studies. Published meta-analyses are based on retrospective data. There is little evidence supporting the practice of random/non-directed oropharyngeal biopsies. Available evidence supports palatine tonsillectomy and tongue base mucosectomy compared to deep tissue biopsies.

p16 immunohistochemistry for primary tumor detection in HPV-positive squamous cell carcinoma of unknown primary.

PURPOSE: To examine the potential benefit of reevaluation of original slides and p16 immunohistochemistry (IHC) of tonsillectomy specimens for primary tumor identification in cases of human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck of unknown primary. MATERIALS AND METHODS: Through a retrospective review, we identified all patients 18 or older who presented at our institution from 2003 to 2015 with histologically confirmed HPV-positive SCC in a cervical lymph node with unidentified primary tumor after initial workup. For patients for whom specimens were available, an expert head and neck pathologist re-reviewed original hematoxylin and eosin (H&E) slides to confirm absence of tumor and performed p16 IHC and deep sectioning of tissue blocks to identify potential tumor foci. RESULTS: Among 735 patient records assessed, 80 were HPV-positive SCC with unknown primary, 28 of which did not have a primary tumor identified, and 20 with original specimens available. Upon re-review of 103 original H&E slides, invasive SCC was identified for 2 patients. Deep sectioning and p16 IHC did not identify additional primary tumors. CONCLUSION: Re-review of original slides by an expert head and neck pathologist, but not p16 staining or deeper H&E sections, was able to identify additional tumors.

Human papillomavirus circulating tumor DNA: a diagnostic tool in squamous cell carcinoma of unknown primary-a pilot study.

Introduction: Neck mass is the most common presentation of human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinoma (OPSCC). Recently, circulating tumor HPV-DNA (ctHPVDNA) assays have been developed to detect active OPSCC. This pilot study investigates the diagnostic accuracy of ctHPVDNA in establishing HPV status for known vs. unknown OPSCC presenting as a neck mass. Methods: A single-institution pilot study was conducted on all patients with OPSCC presenting as a neck mass between 2021 and 2022. The diagnostic accuracy of ctHPVDNA was compared to that of standard diagnostic procedures used to obtain HPV status according to the American Society of Clinical Oncology (ASCO) guideline for squamous cell carcinoma of unknown primary (SCCUP). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ctHPVDNA were calculated. Results: A total of 27 patients were included; 70.4% were current or former smokers, 48.1% (N = 13) had identifiable primaries, and 51.9% (N = 14) had SCCUP. Four patients with known primaries required operative direct laryngoscopy with biopsy (DLB) to establish HPV status. Two patients with SCCUP underwent diagnostic transoral robotic surgery (TORS) to establish HPV status and localize the primary. Twelve patients underwent therapeutic TORS and neck dissection. The gold standard for HPV status was based on final histopathologic p16 or HPV in situ hybridization (ISH) staining during workup/treatment. ctHPVDNA had 95.8% sensitivity, 100% specificity, 100% PPV, and 75% NPV in predicting HPV-positive OPSCC in the whole sample. Binary logistic regression model using ctHPVDNA results to predict HPV-positive OPSCC was significant (-2 log likelihood = 5.55, χ2 = 8.70, p <.01, Nagelkerke's R squared = .67). Among patients with identifiable primaries, all patients had HPV-positive tumors on final pathology, and ctHPVDNA was positive in 100%. In the unknown primary patients, ctHPVDNA had 90.9% sensitivity, 100% specificity, 100% PPV, and 75% NPV. Discussion: ctHPVDNA demonstrated good diagnostic accuracy for both known and unknown primaries. Incorporation of ctHPVDNA into the diagnostic algorithm for SCCUP may reduce the need for multiple procedures to establish HPV status.

An Autopsy Case of Pulmonary Tumor Emboli Due to Metastatic Squamous Cell Carcinoma.

A 74-year-old man with chronic obstructive pulmonary disease on home oxygen and coronary artery disease was transferred from an outside facility to obtain an inguinal lymph node biopsy to rule out malignancy. He underwent an uncomplicated procedure and was discharged the same day. While waiting for transportation, he had sudden-onset dyspnea and collapsed. After resuscitation, patient had return of spontaneous circulation and was admitted but was provided comfort care and soon expired. Autopsy showed metastatic squamous cell carcinoma with multiple bilateral tumor emboli. Pulmonary tumor embolism is a rare cause of dyspnea in cancer population. Most of the cases are diagnosed with autopsy after sudden death; however, few cases have been reported antemortem. Tumor embolism is rare and difficult to diagnose without an autopsy with a poor outcome.

Squamous Cell Carcinoma of Unknown Primary: Multiple Skeletal Metastases Without Detectable Visceral Lesions.

The appropriate diagnosis of carcinoma of unknown primary can be challenging for physicians, especially when they cannot apply a logical and ordered diagnostic process due to the unorthodox clinical characteristics. Here, we report the case of a 75-year-old woman presenting with multiple skeletal metastases with neither detectable visceral lesions nor site-specific distribution. Histological examination of a skeletal biopsy specimen unexpectedly revealed squamous cell carcinoma (SCC). Further specialized investigations led to the diagnosis of SCC of unknown primary. This case highlights the difficulty of the clinical differential diagnostic process in the quest for the occult primary tumor site.

Human Papillomavirus (HPV)-Associated Squamous Cell Carcinoma In situ With Positive p16 and Ki-67 Immunohistochemical Stains in a Young Immunocompetent Patient.

There is an oncogenic role of human papillomavirus (HPV) in the development of premalignant and malignant skin cancers, especially squamous cell carcinomas (SCCs). Some of the major risk factors for SCC include older age, fair skin types, immunosuppression, ultraviolet radiation (UVR), history of epidermodysplasia verruciformis (EV), and co-carcinogenesis by the HPV. Our case report exemplifies a unique case of a low-risk, 34-year-old female who developed an HPV-associated squamous cell carcinoma in situ (SCCIS) on her left palmar hand, despite having none of the contributing risk factors. The biopsy also showed full-thickness keratinocyte atypia and increased mitotic activity throughout all the layers of the epidermis. Immunohistochemical stains showed strong and diffuse nuclear staining of p16 and Ki-67 throughout the SCCIS, confirming HPV etiology. We speculate that tumor development in our patient relied on the combined effects of UVR exposure, localized immunosuppression, and the co-carcinogenic effects of HPV infection.

Significance of the Neutrophil-to-Lymphocyte Ratio in p16-Negative Squamous Cell Carcinoma of Unknown Primary in Head and Neck.

Objective: The neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with survival in solid malignancies. The main goal was to evaluate the prognostic significance of the NLR in patients with p16-negative squamous cell carcinoma of unknown primary (SCCUP) in head and neck. Methods: The association between the NLR and clinical pathologic variables was evaluated by the chi-square test. The primary endpoint of interest was disease-specific survival (DSS). Univariate and Coxmodel analyses were used to evaluate prognostic factors. Results: A total of 153 patients were included in the analysis. Cancer cachexia was noted in 10 patients. The mean NLR value was 3.9 (range: 1.4-8.3). A high NLR was significantly associated with cancer cachexia development. The 5-year DSS rate was 58%. In patients with NLRs varying from 1.4 to 3.7, the 5-year DSS rate was 71%; in patients with NLRs varying from 3.7 to 6.0, the 5-year DSS rate was 57%; in patients with NLRs varying from 6.0 to 8.3, the 5-year DSS rate was 39%, and the difference was significant (p = 0.001). Further Cox model analysis confirmed the independence of the NLR in predicting survival. Conclusions: In patients with p16-negative SCCUP, an NLR ≥ 6.0 is significantly associated with worse prognosis.

FDG PET/CT for metastatic squamous cell carcinoma of unknown primary of the head and neck.

OBJECTIVE: The role of FDG PET/CT is uncertain in squamous cell carcinoma of unknown primary (SCCUP). Published data are limited by heterogeneity of pathology, varied diagnostic criteria, and small sample size. MATERIALS/METHODS: This retrospective study was conducted in 40 patients who had FDG PET/CT for SCCUP. Prior to PET/CT, patients had underwent standard clinical evaluations including flexible rhinolaryngoscopy. The majority of the patients had anatomic imaging. All subjects had histopathological investigations, and follow-up data after PET/CT. RESULTS: FDG PET/CT detected the primary in 16 of 40 patients (40%), and the most common locations of the primary were in the base of the tongue, palatine tonsil, and hypopharynx. There were 10 false positive and 6 false negative PET/CT scans. There was no difference in the mean SUVs of the suspected primary lesions between true and false positive groups. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy of FDG PET/CT for SCCUP in this patient cohort were 72.7% (16/22), 44.4% (8/18), 61.5% (16/26), 57.1% (8/14), and 60% (24/40), respectively. The tonsil was the site with the most false positive and false negative findings. CONCLUSIONS: FDG PET/CT might be an effective single shot of whole-body imaging for detection of the primary in SCCUP. Low specificity remained the most notable weakness of FDG-PET in work-up for SCCUP. In addition to varied physiologic uptake or inflammatory related uptake in the common locations of the primary, the image indication bias might be another significant contributor of high false positive rate.

Metastatic Squamous Cell Carcinoma in the Gallbladder Fossa Complicated by a Duodenal Fistula.

Cancer of unknown primary is defined as a metastatic disease present in the absence of an identifiable primary site of origin. Squamous cell carcinoma (SCC) of unknown primary is a relatively uncommon subtype that usually involves metastases to the cervical or inguinal lymph nodes. We present a rare case of SCC of unknown primary metastasizing to the gallbladder fossa and creating a duodenal fistula. This case highlights the rarity of SCCs in the gallbladder region and the risks posed by chemotherapy in patients with gastrointestinal fistulas.

The Impact of a Stepwise Approach to Primary Tumor Detection in Squamous Cell Carcinoma of the Neck With Unknown Primary.

OBJECTIVES/HYPOTHESIS: To examine the cumulative effect of diagnostic steps for primary tumor identification in patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP), including lingual tonsillectomy, and the impact of primary tumor identification on subsequent treatment. STUDY DESIGN: Retrospective analysis. METHODS: We reviewed the records of 110 patients diagnosed with HNSCCUP between 2003 and 2015. Results of diagnostic imaging (fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]), tumor detection with direct laryngoscopy with biopsies, palatine tonsillectomy, and transoral robotic surgery (TORS) lingual tonsillectomy were recorded. Associations between demographic and treatment variables with overall survival (OS) and progression-free survival (PFS) were modeled with Cox proportional hazards models. RESULTS: FDG-PET/CT was suspicious for a primary site in 23/77 (30%) patients. Direct laryngoscopy identified a primary tumor in 34/110 patients (31%). Forty-seven patients underwent palatine tonsillectomy, which identified 17 primaries (36%), yielding a cumulative primary tumor identification of 51/110 (46%). Fourteen patients underwent TORS lingual tonsillectomy, which identified eight primaries (57%), resulting in a cumulative identification of 59/110 (53%). The detection rate increased from 28/63 (44%) to 31/47 (66%) after the addition of TORS lingual tonsillectomy to our institutional approach. Detection rates varied by HPV status. Primary tumor identification altered subsequent radiation planning, as patients with an identified primary tumor received radiation to a smaller volume of tissue than did those without an identified primary tumor. However, there was no significant association between primary tumor identification and OS or PFS. CONCLUSIONS: A stepwise approach to primary tumor identification identifies a primary tumor in a majority of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1610-1616, 2019.

Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: Updates on efficacy, surgical technique and margin status.

IMPORTANCE: Management of cervical unknown primary squamous cell carcinoma (CUP) has evolved with the introduction of transoral robotic surgery (TORS). OBJECTIVES: 1. To describe the efficacy of TORS lingual and palatine tonsillectomy in identifying the primary site of malignancy. 2. To explore how the extent of surgery affects diagnostic yield. 3. To report margin status of TORS resections. DESIGN, SETTING AND PARTICIPANTS: A retrospective, single-center cohort study utilizing a prospectively collected database of CUP patients in a high-volume tertiary referral center. Patient underwent operative laryngoscopy plus TORS as clinically indicated. MAIN OUTCOMES AND MEASURES: Primary end point was successful identification of the primary. The extent of surgery and margin status were also examined. RESULTS: From 2010-2016, 64 patients with CUP were treated. The primary tumor was found in 51 patients (80%). Fourteen patients (22%) were identified with operative laryngoscopy alone. Fifty patients underwent TORS lingual tonsillectomy ± palatine tonsillectomy with 37 primary tumors identified (74%). The primary was located in the lingual tonsil in 32 patients (86%) and palatine tonsil in 5 patients (10%, p<0.001). Negative margins were achieved in 19 patients (51%). The deep margin was the most commonly positive margin (47%, p=0.049). CONCLUSION AND RELEVANCE: Operative laryngoscopy with TORS is efficacious, localizing the primary in 80% of patients. If a margin was positive, it was most commonly the deep margin. This study provides valuable information that can help standardize surgical technique, further increasing the diagnostic yield and decreasing the negative margin rate of TORS for CUP.