Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline

Maghami, Ellie; Ismaila, Nofisat; Alvarez, Adriana; Chernock, Rebecca D.; Duvvuri, Umamaheswar; Geiger, J.L.; Gross, Neil D.; Haughey, Bruce H.; Paul, Doru; Rodriguez, Cristina P.; Sher, David J.; Stambuk, Hilda E.; Waldron, John; Witek, M.E.; Caudell, J.J.

doi:10.1200/jco.20.00275

Cited by 101 publications

(152 citation statements)

References 165 publications

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“…For patients with bilateral lymphadenopathy, if a primary site is not confirmed on endoscopic examination, then the surgeon may perform unilateral lingual tonsillectomy on the side with the greater nodal burden and may perform contralateral lingual tonsillectomy if the ipsilateral procedure fails to identify a primary. Bilateral palatine tonsillectomy after bilateral lingual tonsillectomy should be avoided (9).…”

Section: Benefits Of Tonsillectomymentioning

confidence: 99%

Role of Tonsillectomy in the Management of Carcinomas of Unknown Primary of the Head and Neck: A Retrospective Study Based on p16 Analysis

et al. 2020

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Purpose: To evaluate the impact of tonsillectomy on the detection of the primary tumor, based on p16 immunohistochemistry analysis, in patients with cervical unknown primary of squamous cell carcinoma (SCC-CUP). Methods: This was a retrospective study of 63 patients, included from January 2008 to December 2017 in a single institution. All patients had an initial assessment with physical examination, CT scan of the neck and chest, whole body FDG-PET CT, and endoscopy under general anesthesia, which failed to determine the primary tumor. Results: Forty-seven out of the 63 patients had an ipsi-or bilateral tonsillectomy which revealed 12 tonsil cancers (26%). The tonsil primary was ipsilateral to positive nodes in 10 cases, contralateral in 1 case and, in 1 case, the patient had bilateral neck involvement. The analysis of the p16 status was carried out in 41/63 patients (65%). Among the 32 patients who had a p16 analysis and tonsillectomy, the rate of primary detection was 59% (10/17) for p16-postives and 0% (0/15) for p16-negatives (p < 0.001). Conclusion: These results suggest that an extended work-up should be systematically proposed including bilateral tonsillectomy (+/-mucosectomy of the base of tongue) in SCC-CUP p16-positive patients but not in p16-negatives.

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Section: Benefits Of Tonsillectomymentioning

confidence: 99%

Role of Tonsillectomy in the Management of Carcinomas of Unknown Primary of the Head and Neck: A Retrospective Study Based on p16 Analysis

et al. 2020

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“…27,28 In this study, P16 was strongly positive in a metastatic urothelial carcinoma, which was excluded. 1,4 More than 80% of the cases had concurrent core biopsy, and almost half of the cases underwent both core biopsy and surgical follow-up. FNA was the sole diagnostic method in only four cases.…”

Section: Statisticsmentioning

confidence: 99%

“…Of note, according to the ASCO, HR-HPV testing is not required to be repeated on the primary tumour if a level II or III neck lymph node with metastatic HNSCC is P16+/HR-HPV+. 4…”

Section: Limitationsmentioning

confidence: 99%

“…4 It also recommends HR-HPV testing non-routinely on SCC metastases at other nodal levels when clinical suspicion is high. 4 The testing may be performed on the primary tumour or a clinically compatible regional lymph node. 16 The more established testing methods such as hybrid capture 2 assay.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies have even shown that HPV-RNA ISH has a higher sensitivity compared to other methods for HPV testing in HNSCC 25. The ASCO recommends Epstein-Barr encoding region (EBER) ISH testing in HPV negative HNSCC of unknown primary 4. In this study, EBER ISH testing was performed on two excluded cases, which were presented as enlarged neck lymph nodes and were diagnosed nasopharyngeal carcinoma, one was focally positive for P16 and both cases wereHPV-.…”

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confidence: 98%

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Diagnostic utility of high‐risk human papillomavirus mRNA in situ hybridisation in squamous cell carcinoma of unknown primary in the head and neck and implementing American Society of Clinical Oncology guideline recommendations

2020

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Introduction: The American Society of Clinical Oncology (ASCO)-endorsed College of American Pathologists guideline recommends high-risk human papillomavirus (HPV) testing for metastatic squamous cell carcinoma (SCC) of lymph nodes level II/ III of unknown primary. Herein, the performance of HPV-RNA in situ hybridisation (ISH) in detection of HPV-related SCC is evaluated implementing the ASCO guideline recommendations. Methods: Eighty head and neck (HN) SCC fine needle aspirations, which utilized HPV-RNA ISH/P16, were evaluated at Johns Hopkins Hospital (2015-2018) to investigate their performance and concordance with histology. The results were compared to a prior study of 59 HNSCCs, which HPV-DNA ISH. Results: Of the 80 reviewed fine needle aspirations, 65 (50 male, 15 female) were included. The mean age was 63.2 ± 14.0 years. The most common site was neck lymph nodes (47, 72.3%). Fifty-five cases (84.6%) were accompanied by concurrent core biopsy, and 48 cases (59.4%) had surgical follow-ups. HPV-RNA ISH was positive in 44 (67.7%), and P16 was strongly positive in 46 (70.8%). The HPV-RNA ISH/ P16 concordance rate was 92.3% on cytology material. The cytology/surgical concordance rate for HPV-RNA ISH was 88.9% (16/18). There was a discordance between the results in five cases (7.7%; HPV-RNA ISH-/P16+). Conclusion: HPV-RNA ISH is a robust and reliable method for detecting HPV-related HNSCC on cytology material showing concordance rate of 92.3% between HPV-RNA ISH and P16, which is a sensitive but non-specific marker. Compared to HPV-DNA ISH, HPV-RNA ISH reproducibly identifies HPV-related HNSCC with fewer discrepancies between cytology and histology. The findings of this study are in agreement with the ASCO recommendations.

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Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Ferrandino

Chen

Kappauf

et al. 2023

JAMA Otolaryngol Head Neck Surg

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ImportanceThere is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue–modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials.ObjectiveTo establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting.Design, Setting, and ParticipantsThis retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy.Main Outcomes and MeasuresPer-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing.ResultsOf 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days.Conclusions and RelevanceThis cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay’s performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

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Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline

Cited by 101 publications

References 165 publications

Role of Tonsillectomy in the Management of Carcinomas of Unknown Primary of the Head and Neck: A Retrospective Study Based on p16 Analysis

Role of Tonsillectomy in the Management of Carcinomas of Unknown Primary of the Head and Neck: A Retrospective Study Based on p16 Analysis

Diagnostic utility of high‐risk human papillomavirus mRNA in situ hybridisation in squamous cell carcinoma of unknown primary in the head and neck and implementing American Society of Clinical Oncology guideline recommendations

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

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