Key Points
Question
What is the diagnostic value of intraoperative pathology consultation in transoral robotic surgery (TORS)/oropharyngectomy for oropharyngeal squamous cell carcinoma with unknown primary tumors?
Findings
In this case series of 47 adult patients with human papillomavirus (HPV)–associated squamous cell carcinoma with unknown primary tumors treated with TORS, intraoperative pathology consultation had limited sensitivity (49%) and negative predictive value (34%) in locating the primary tumor and did not influence need for radiotherapy with or without chemotherapy or a second procedure.
Meaning
These findings suggest that there may be little practical utility in performing routine intraoperative consultation for diagnostic oropharyngectomy specimens.
This case series study assesses the sensitivity, specificity, and predictive values of primary tumor localization through intraoperative pathology consultation during transoral robotic surgery for human papillomavirus–associated squamous cell carcinoma for unknown primary tumors.
Abstract
Importance
Current guidelines recommend intraoperative frozen section(s) during diagnostic surgery for squamous cell carcinoma for unknown primary tumors (SCCUP).
Objective
To determine the utility of intraoperative pathology consultation during transoral robotic surgery (TORS) in localizing primary tumors and influencing need for adjuvant therapy.
Design, Setting, and Participants
A retrospective case series including 47 adult patients with human papillomavirus (HPV)–associated SCCUP who underwent TORS/oropharyngectomy between January 2016 and February 2023 was carried out at a single tertiary care hospital. The analysis took place on May 13, 2024.
Exposures
Nodal stage, tonsillectomy history, extranodal extension (ENE).
Main Outcomes and Measures
Intraoperative pathology consultation and final pathology results were compared with surgical outcomes, including margin revision, need for second procedure and/or radiation with or without chemotherapy.
Results
This study included 47 adult patients. Mean (range) age was 61 (41-79) years; patients were mostly men (37 [79%]). Overall, primary tumors were identified in 37 patients (79%), including all cases with positive nodes involving more than 1 neck level. Patients whose primary tumor was not found tended to have tobacco use history (8/10 vs 13/37 [35%]; difference, 45%; 95% CI, 16%-74%) and absence of ENE (8/10 vs 15/37 [41%]; difference, 39%; 95% CI, 10%-68%). Primary tumor was identified intraoperatively in 18 of 37 patients (49%). SCCs identified intraoperatively were significantly larger than SCCs found on permanent sections only: mean (SE), 1.2 (0.13) cm vs 0.5 (0.1) cm (difference, 0.7 cm; 95% CI, 0.53-1.94). The sensitivity, specificity, positive predictive value, and negative predictive value of intraoperative consultation was 49% (95% CI, 33%-64%), 100% (95% CI, 100%-100%), 100%, and 34% (95% CI, 19%-53%), respectively. Margins were revised in 11 of 18 patients (61%) whose primary tumor was identified intraoperatively (during original procedure) and in 3 of 19 patients (16%) whose primary tumor was identified on permanent pathologic findings only (during a second procedure) (11/18 [61%] vs 3/19 [16%]; difference, 45%; 95% CI, 17%-73%). However, there was no significant difference in the use of adjuvant radiotherapy with or without chemotherapy or need for a second procedure based on intraoperative primary tumor localization.
Conclusion and Relevance
In this case series study, the sensitivity and negative predictive value of intraoperative pathology consultation among 47 patients was less than 50%. Given the lack of influence on the need for radiotherapy with or without chemotherapy or second procedure, the practical utility of routine intraoperative frozen section requires further scrutiny.
Introduction
The global incidence of patients with metastatic squamous cell carcinoma to the cervical lymph nodes with an unknown primary tumor (SCCUP) is estimated to be 3% to 5%.1,2,3 Most newly presenting SCCUPs are human papillomavirus (HPV) associated, which typically corresponds with occult oropharyngeal primary tumors.3,4,5,6 Localization of primary tumor advances cancer staging, refines treatment approach, and is associated with improved cause-specific and disease-free survival.4 Tumor localization may enable focused surgical or radiation therapy, resulting in excellent locoregional control while reducing risk for long-term morbidities associated with wide-field radiation such as cranial nerve palsies, xerostomia, dysphagia, laryngeal dysfunction, and esophageal strictures.2,4,7,8 Patients usually present with cervical lymphadenopathy with biopsy or fine needle aspiration (FNA)–proven squamous cell carcinoma (SCC) in the absence of obvious upper aerodigestive primary. If the primary tumor remains occult after thorough history, physical examination, endoscopy, and imaging studies, diagnostic efforts then focus on localization via additional oropharyngeal biopsies and diagnostic ipsilateral tonsillectomy or base of tongue (BOT) resection. One way this can be accomplished is through transoral robotic surgery (TORS).
Compared with traditional oral surgical approaches, which are often more technically challenging with poor visualization and transcervical approaches that drastically increase morbidity, TORS provides remarkable visualization and high tumor localization accuracy, with rates ranging from 64% to 90%.1,9,10,11,12,13,14 In current TORS for SCCUP practice, biopsies and partial resections are commonly taken from suspicious primary sites such as the ipsilateral palatine tonsil, BOT, and glossotonsillar sulcus. The surgeon delivers and anatomically orients the specimen(s) for intraoperative pathology consultation, seeking to confirm tumor presence and use the pathologist’s intraoperative report to guide the remaining operative approach.15,16 In the setting of unilateral neck disease, the surgeon first seeks to localize the tumor through an ipsilateral palatine tonsillectomy followed by ipsilateral BOT resection if palatine evaluation has negative results.15,16 Current guidelines recommend palatine tonsil and BOT specimens be entirely processed for intraoperative frozen section evaluation and margin assessment.15 However, this recommendation is based on studies that included extraoropharyngeal sites and compared margin assessment accuracy in frozen vs permanent sections not specific to SCCUP or HPV-associated disease, each of which beget unique challenges.17,18,19 Although intraoperative consultation is used to improve chances of tumor localization, in practice, this leads to longer operation times, increased cost, and additional pathology team effort. Furthermore, the sensitivity, specificity, and predictive values of this practice during TORS specific to HPV-associated SCCUP remains insufficiently explored.
The aim of this study was to assess the sensitivity, specificity, and predictive values of primary tumor localization through intraoperative pathology consultation during TORS for HPV-associated SCCUP. In addition, we aimed to establish whether intraoperative pathology consultation changes the extent of diagnostic oropharyngectomy and the rate of and/or indications for adjuvant therapy.
Methods
Study Population
This study was approved by the University of Pittsburgh institutional review board. Informed consent was obtained from all patients before data entry into a clinical research database. We performed a retrospective case series of adult patients aged 18 years or older who underwent TORS, including tonsillectomy and/or BOT excision, for SCCUP at a single tertiary academic center between January 1, 2016, and February 1, 2023. Patients were classified as having SCCUP based on presentation with a neck mass without definitive primary tumor on clinical examination, imaging studies including positron emission tomographc (PET) and computed tomographic (CT) scans of neck with contrast, and direct laryngoscopy with oropharyngeal biopsies. Inclusion criteria also included neck mass FNA or core biopsy positive results for HPV-associated SCC and diagnosis of HPV association via p16 positive results on immunohistochemistry staining and/or high-risk HPV in situ hybridization. P16 and HPV testing were completed as part of clinical workflow and were performed as previously described.20 Patients presenting with a prior head and neck cancer diagnosis or distant metastases were excluded.
Data Collection
Demographic information including patient age, sex, and race and ethnicity was collected. Race and ethnicity as classified and defined by the patient was included to elucidate whether it influenced primary or secondary outcomes. History of tobacco and alcohol use were recorded. Alcohol use was considered extensive if 14 or more drinks per week for men and 7 or more drinks per week for women. Laterality, level of lymph node neck involvement and history of tonsillectomy as a child were gathered at the initial visit to the otolaryngologist. Clinical and pathologic staging was determined for each patient following the American Joint Committee on Cancer (AJCC) 8th edition guidelines.21 All intraoperative consultations were performed by subspecialty-trained head and neck pathologists. Comprehensive gross examination, including orientation, inking, and sectioning of the specimen followed by review of each tissue slice for areas distinct from background normal tissue (eg, discoloration, firmness), was the initial component of every consultation. Operative details collected included procedure(s) performed, intraoperative specimens sent to the pathology department, and findings of intraoperative consultation. All patients had ipsilateral neck disease and, therefore, the following operative workflow was used: ipsilateral palatine tonsil resection for intraoperative consultation (if palatine tonsil tissue present). If negative, the ipsilateral BOT was resected for intraoperative consultation or for permanent (final) assessment only. Localization of primary tumor on intraoperative consultation of palatine tonsil would guide decision to not resect BOT and on whether margin revision for palatine tonsillectomy was needed. Intraoperative consultation was considered to change operation if one or the combination of the following took place: (1) primary SCC was identified and further surgical search for primary tumor was aborted; (2) positive margins were found and intraoperatively revised; and (3) if ipsilateral oropharyngectomy (palatine or BOT tonsillectomy) failed to identify primary tumor and contralateral oropharyngectomy was performed. Permanent pathologic results were recorded, including specimen-driven margin status, extranodal extension (ENE), perineural invasion (PNI), lymphovascular invasion (LVI), and final pathologic tumor stage. A second procedure was performed for neck dissection, additional oropharyngectomy, and margin revision.
Statistical Analysis
Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to determine whether intraoperative consultations were congruent with final pathologic results. Effect sizes for categorical and continuous variables were calculated as the difference in proportions and the difference in means (Cohen d), respectively, with corresponding 95% CIs. All statistical analysis was performed using Stata statistical software (version 17; StataCorp). The analysis took place on May 13, 2024.
Results
This study included 47 adult patients. The mean (range) age was 61 (41-79) years (Table 1). Most patients were men (37 [79%]; 10 [21%] women), did not use tobacco (26 [55%]), or extensive alcohol (42 [89%]). Forty six patients were White. Clinical stages included cN1 (43 [91%]) and cN2 (4 [9%]). Overall, primary oropharyngeal SCC was identified in 37 patients (79%), including all cases with positive lymph nodes involving more than 1 neck level (levels 2 and 3, n = 7 [15%]) or level 4 lymph nodes (n = 2 [4%]). All patients presented with ipsilateral neck disease. Patients whose primary tumor was not found tended to have tobacco use history (8/10 [80%] vs 13/37 [35%]; difference, 45%; 95% CI, 16%-74%) and absence of lymph node ENE (as eventually determined by pathologic examination) (8/10 vs 15/37 [41%]; difference, 39%; 95% CI, 10%-68%) (Table 1). Of the 17 patients who received tonsillectomy during childhood, 14 (82%) had primary tumors that were identified. Twelve (86%) were found in the ipsilateral BOT, 1 (7%) in the ipsilateral glossotonsillar sulcus, and 1 (7%) in the bilateral BOT. Three patients underwent tonsillectomy within 2 months of TORS for SCCUP. All 3 tonsillectomy specimens were microscopically examined in entirety and were benign. TORS identified primary tumors in all 3 of these patients, with 2 found in the ipsilateral glossotonsillar sulcus and 1 in the ipsilateral BOT. There was no difference in age, sex, extensive alcohol use, change in operation based on intraoperative findings, or requirement for a second procedure or adjuvant radiotherapy and/or chemotherapy (Table 1).
Table 1. Demographic Characteristics of Patients with Unknown Primary Head and Neck Squamous Cell Carcinoma.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Total (N = 47) | Primary tumor found | Effect size (95% CI) | ||
| Yes (n = 37) | No (n = 10) | |||
| Sex | ||||
| Female | 10 (21) | 7 (19) | 3 (30) | 0.11 (−0.20 to 0.42) |
| Male | 37 (79) | 30 (81) | 7 (70) | |
| Age, mean (range), y | 61 (41-79) | 61 (41-79) | 62 (55-71) | 0.12 (−0.58 to 0.82) |
| Tobacco use history | ||||
| Yes | 21 (45) | 13 (35) | 8 (80) | −0.45 (−0.74 to −0.16) |
| No | 26 (55) | 24 (65) | 2 (20) | |
| Extensive alcohol use history | ||||
| Yes | 5 (11) | 3 (8) | 2 (20) | −0.12 (−0.38 to 0.14) |
| No | 42 (89) | 34 (92) | 8 (80) | |
| Tonsillectomy as a child | ||||
| Yes | 17 (36) | 13 (35) | 4 (40) | −0.05 (−0.39 to 0.29) |
| No | 30 (64) | 24 (65) | 6 (60) | |
| Sample sent intraoperatively | ||||
| Biopsy | 6 (13) | 2 (5) | 4 (40) | −0.35 (−0.66 to −0.04) |
| Main specimen with or without biopsy | 41 (87) | 35 (95) | 6 (60) | |
| Tumor stage, pT | ||||
| 0 | 10 (21) | 0 | 10 (100) | NA |
| 1 | 36 (77) | 36 (97) | 0 | |
| 2 | 1 (2) | 1 (3) | 0 | |
| Nodal stage, pN | ||||
| 1 | 40 (85) | 33 (89) | 7 (70) | 0.19 (−0.11 to 0.49) |
| 2 | 7 (15) | 4 (11) | 3 (30) | |
| Presence of extranodal extension | ||||
| Present/indeterminate | 24 (51) | 22 (59) | 2 (20) | 0.39 (0.10 to 0.68) |
| Absent | 23 (49) | 15 (41) | 8 (80) | |
| Level of positive nodes | ||||
| II | 33 (70) | 25 (68) | 8 (80) | −0.12 (−0.41 to 0.17) |
| III with or without II with or without IV | 14 (30) | 12 (32) | 2 (20) | |
| Number of levels of positive nodes | ||||
| 1 | 38 (81) | 28 (76) | 10 (100) | −0.24 (−0.38 to −0.10) |
| >1 | 9 (19) | 9 (24) | 0 (0) | |
| Required second procedure | ||||
| Yes | 15 (32) | 12 (32) | 3 (30) | 0.02 (−0.30 to 0.34) |
| No | 32 (68) | 25 (68) | 7 (70) | |
| Intraoperative findings changed operation | ||||
| Yes | 21 (45) | 16 (43) | 5 (50) | −0.07 (−0.42 to 0.28) |
| No | 26 (55) | 21 (57) | 5 (50) | |
| Adjuvant therapy | ||||
| Radiation with or without chemoradiation | 34 (72) | 29 (78) | 5 (50) | 0.28 (−0.06 to 0.62) |
| Observation | 13 (28) | 8 (22) | 5 (50) | |
Abbreviation: NA, not applicable.
Intraoperative localization of primary occurred in 18 of the 37 patients (49%) whose primary tumor was identified (Table 2). Procedures performed and frequency of finding primary tumor, intraoperatively or on permanent sections only, are shown in Table 3. One patient had multifocal bilateral BOT primary tumors with only 1 focus identified intraoperatively. This patient was counted toward those in whom a primary tumor was found on permanent section only. All other 37 patients had a single identified primary ipsilateral to cervical metastasis, most commonly in the BOT (n = 24/37 [65%]), followed by the ipsilateral palatine tonsil and the glossotonsillar sulcus (n = 10/37 [27%]; n = 3/37 [5%], respectively). SCCs identified intraoperatively were significantly larger than SCCs found on permanent sections only: mean (standard error [SE]), 1.2 cm (0.1 cm) vs 0.5 cm (0.1 cm) (difference, 0.7 cm; 95% CI, 0.5-1.9). Although a primary tumor was found in all patients who had nodal burden in more than 1 neck level, this was not associated with a greater likelihood of intraoperative localization of primary tumor (4/18 [22%] vs 6/19 [32%]; difference 9%; 95% CI, −6% to 25%).
Table 2. Clinical and Pathologic Features of Cases Where Primary Was Found, Intraoperatively or on Permanent Pathologic Findings.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Tumor found intraoperatively (n = 18) | Tumor found on permanent sections only (n = 19) | Effect size (95% CI) | ||
| Location of tumor | Palatine tonsil | 4 (22) | 6 (32) | −0.10 (−0.38 to 0.18) |
| Base of tongue | 12 (67) | 12 (63) | 0.04 (−0.27 to 0.35) | |
| Glossotonsillar sulcus | 2 (11) | 1 (5) | 0.06 (−0.11 to 0.23) | |
| Size, (mean [SE]), cm | ≤0.5 cm | 1 (0.3 [0]) | 11 (0.3 [0.1]) | 1.24 (0.53 to 1.94) |
| >0.5 cm | 17 (1.3 [0.3]) | 8 (1 [0.2]) | ||
| Margin statusa | Positive | 4 (22) | 7 (37) | −0.15 (−0.44 to 0.14) |
| Negative | 14 (78) | 12 (63) | ||
| Revision of marginb | Yes | 11 (61) | 3 (16) | 0.45 (0.17 to 0.73) |
| No | 7 (39) | 16 (84) | ||
| Side of tumor | Right | 9 (50) | 9 (47) | 0.03 (−0.29 to 0.35) |
| Left | 9 (50) | 10 (53) | ||
| Tobacco use history | Yes | 9 (50) | 4 (21) | 0.29 (−0.005 to 0.58) |
| No | 9 (50) | 15 (79) | ||
| Tonsillectomy as a child | Yes | 6 (33) | 7 (37) | −0.04 (−0.35 to 0.27) |
| No | 12 (67) | 12 (63) | ||
| Presence of extranodal extension | Yes | 10 (56) | 12 (63) | −0.07 (−0.39 to 0.25) |
| No | 8 (44) | 7 (37) | ||
| Sample tissue sent intraoperatively | Biopsy | 0 | 2 (11) | −0.11 (−0.25 to 0.03) |
| Main specimen with or without biopsy | 18 (100) | 17 (89) | ||
| Required second procedure | Yes | 7 (39) | 6 (32) | 0.07 (−0.24 to 0.38) |
| No | 11 (61) | 13 (68) | ||
| Adjuvant therapy | Radiation with or without chemoradiation | 14 (78) | 14 (74) | 0.04 (−0.24 to 0.31) |
| Observation | 4 (22) | 5 (26) | ||
Intraoperatively, if found, and otherwise on permanent sections; margin status not requested in 1 case.
Intraoperatively, if found and margins were positive or close (0.1-0.2 mm); or as a second procedure if found on permanent sections only.
Table 3. Procedures Performed and Incidence of Finding Primary Tumor: Intraoperatively, on Permanent Sections Only, or Not Found.
| Palatine tonsillectomy | Base of tongue resection | Total patients, No. (%), (N = 47) | No. | ||
|---|---|---|---|---|---|
| Primary tumor found | Primary tumor found intraoperatively. | Not found | |||
| Bilateral | Bilateral | 4 (9) | 2 | 0 | 2 |
| Bilateral | Unilateral | 8 (17) | 5 | 2 | 3 |
| Unilateral | Bilateral | 2 (4) | 2 | 1 | 0 |
| Unilateral | Unilateral | 9 (19) | 7 | 5 | 2 |
| Unilateral | None | 4 (9) | 4 | 2 | 0 |
| Bilateral | None | 3 (6) | 3 | 2 | 0 |
| None | Bilateral | 5 (11)a | 4 | 1 | 1 |
| None | Unilateral | 12 (26)a | 10 | 5 | 2 |
All with history of tonsillectomy as a child.
Found primary tumors were located within the ipsilateral oropharynx in all but 1 patient. Only 1 of 9 patients (11%) who underwent bilateral BOT resections was found to have bilateral SCC. This patient had 2 tumors in the bilateral BOT which were 0.3 cm and 0.2 cm in greatest dimension and 3.5 cm to 3.9 cm apart. The larger of these tumors corresponded with ipsilateral neck disease as revealed by bilateral neck dissection.
Specimen type(s) examined intraoperatively varied from oropharyngeal biopsies alone (n = 6), main resection specimens (n = 29), and biopsies followed by main resection specimens (n = 12). When intraoperative consultation on the main resection specimen was requested, frozen sections were obtained in all but 3 cases where gross examination alone occurred.
All but 1 anatomic site found to harbor malignant tumors on permanent sections were examined intraoperatively. That is, in 1 case, intraoperative assessment occurred for the ipsilateral palatine tonsil only, which was benign, with permanent slides of the ipsilateral BOT revealing primary tumor. However, there were just 2 cases in which the entire intraoperative main specimens underwent frozen section analysis. The sensitivity, specificity, PPV, and NPV of intraoperative consultation in all patients was 49% (18/37; 95% CI, 33%-64%), 100% (10/10; 95% CI, 100%-100%), 100% (18/18; 95% CI, 100%-100%), and 34% (10/29; 95% CI, 19%-53%), respectively.
Margins were negative in 12 of 19 tumors (63%) found on permanent sections only and 14 of 18 tumors (78%) found intraoperatively. All cases with negative intraoperative margins remained negative on final pathologic margins. Of the 4 tumors found intraoperatively whose margins were positive, all underwent intraoperative margin revision. In addition, there were 7 cases with technically negative but close margins (<0.1 cm to 0.2 cm) which were immediately revised. Intraoperative localization of primary tumor allowed for immediate assessment of excision adequacy (ie, margin status). Accordingly, margins were revised in 11 of 18 patients (61%) whose primary was identified intraoperatively and in 3 of 19 patients (16%) whose primary tumor was identified on permanent pathologic results only (during a second procedure) (difference, 45%; 95% CI, 17%-73%). In 2 cases (4%), intraoperative revision of close margins yielded resection-negative final margins, which prevented the need for adjuvant radiotherapy with or without chemotherapy (carcinomas showed no other adverse histologic features such as PNI, LVI, or ENE). There was no significant difference in the use of adjuvant radiotherapy and/or chemotherapy or need for a second procedure among patients whose primary tumor was identified intraoperatively or on permanent pathologic findings only (Table 2). There were 6 occasions (13%) where the patient returned to the operating room for neck dissection only. Therefore, we also looked at the influence of intraoperative localization on need for a second procedures involving oropharynx. Even still, the difference was minor (14/34 vs 2/7; difference, 13%; 95% CI, −24% to 50%). In 8 cases (17%), intraoperative consultation resulted in resections of the contralateral oropharynx, which were negative. Three patients with false-negative intraoperative examination results of ipsilateral resections had positive results on permanent pathologic findings. These tumors measured 0.3 cm, 0.3 cm, and 1.2 cm, and all had positive margin status. Overall, intraoperative consultation affected operative approach in 21 cases (44%).
ENE data are presented in Table 2. In our practice, ENE assessment is not accompanied by routine evaluation of the extent of ENE. Information on the extent of ENE was clinically requested on 12 cases. Ten cases had ENE of larger than 0.1 cm (including a soft tissue deposit) and 2 cases were categorized as smaller than 0.1 cm.
Sampling issues (ie, intraoperative vs permanent pathologic discrepancies) were identified in 2 cases. In the first case, a 0.2-cm SCC was identified only on permanent microscopic examination of the entire tonsil and was not present on a representative frozen sections examined intraoperatively. The overall surgery for this patient included bilateral tonsillectomy and bilateral BOT excision. In the second case, a 0.7-cm SCC was identified on frozen section slides only, with no tumor remaining on frozen section remnant processed for permanent sections. Sampling issues involving up to 0.7-cm SCC suggests that intraoperative handling of unfixed tissue (with unavoidable thicker sectioning) may potentially preclude identification of smaller occult oropharyngeal SCCs.
Discussion
In this retrospective case series of 47 patients undergoing TORS for HPV-associated SCCUP, 18 of 37 primary tumors were found intraoperatively, indicating a total intraoperative consultation sensitivity of 49% and NPV of 34% with an overall accuracy of 60%. Intraoperative consultation affected the operative approach in 21 cases (44%), including margin revision and/or extent of surgery (with mixed yield). There were 2 cases (4%) where intraoperative margin revision prevented the need for adjuvant radiotherapy, although the remainder required adjuvant therapy due to other factors such as ENE. Overall, intraoperative tumor localization was not associated with a change in need for adjuvant radiotherapy with or without chemotherapy or for a second procedure.
Primary tumors were localized in 37 patients (79%). While primary tumor was most commonly found in the BOT (24/47 [51%]), 17 patients (36%) had tonsillectomy in childhood. In comparison, in a systematic review that included 12 SCCUP studies and majority HPV associated tumors (range 55%-96%), van Weert et al22 found the pooled TORS tumor localization rate to be 72% (range 17%-90%) with 52% of primary tumors found in the BOT. Similar to our study, Geltzeiler et al9 also showed that most tumors were localized to the BOT (64%) with 32% of their population having undergone tonsillectomy during childhood.
Performance characteristics of intraoperative pathology consultation likely vary with type of specimen submitted for evaluation (biopsy vs main resection specimen) and quality of gross examination and extent of microscopic examination as determined by immediate clinical needs based on surgeon and pathologist collaboration. Even still, when analyzing only those patients whose cases involved some evaluation under frozen section (n = 46/47), these values were essentially unchanged. Importantly, all cases with negative intraoperative margins remained negative on final pathologic margins, indicating that freezing entire specimen(s) would not likely improve margin assessment. To our knowledge, there are no directly comparable studies showing intraoperative consultation accuracy in TORS-managed HPV associated SCCUP. Furthermore, our review of the literature yielded no studies where all SCCUP specimens were frozen in entirety. However, Herruer et al7 assessed the rate of SCCUP localization using PET-CT followed by transoral laser microsurgery (TLM) with intraoperative frozen section consultation. Similar to our study, extent of microscopic examination varied from representative to entirely frozen specimens. Herruer et al7 noted that primary tumor was found intraoperatively in 50 of 61 cases (82%) and on permanent section in 55 of 61 cases (90%). Not including those patients whose primary tumor was detected on PET-CT (n = 27), TLM with intraoperative frozen section consultation localized primary tumors in an additional 23 patients, indicating a sensitivity of 82%. Although the variance of sensitivity between our study and Herruer et al7 may be related to the difference of TORS vs TLM, it is important to note that our study excluded non-HPV SCC, which are typically larger, and any patients with obvious primary tumor on PET-CT whose subsequent direct laryngoscopy with biopsy yielded primary tumors.
One patient was found to have a bilateral primary tumor located in the BOT. Importantly, primary SCC ipsilateral to cervical metastasis was not identified intraoperatively. This initial false-negative result of intraoperative consultation lead to contralateral BOT resection and discovery of a contralateral primary tumor. One patient (11%) who underwent bilateral BOT resections was found to have bilateral SCC. This is consistent with a range between 6% and 12% of contralateral BOT malignant disease reported in various studies.23,24,25 In our series, no contralateral palatine disease was found in the 18 cases that involved bilateral tonsillectomy. This differs from rates of 10% to 23% reported in the literature.14,26,27
Intraoperative consultation likely increased operating time and tissue excision in 8 patients (17%), 3 of whom underwent contralateral resection despite ipsilateral localization on permanent pathologic findings. It is therefore worth considering the mixed yield of routine intraoperative consultation when it may result in unnecessary additional resections.
Limitations
As a single-institution case series, this study has notable limitations. The small sample size prevents making definitive conclusions because the observed estimates were associated with wide CIs. In addition, the generalizability of this study is limited by its focus on tertiary centers, which serve a large geographic area with a mostly White patient demographic. Finally, we acknowledge that our study lacks a comparative group without intraoperative pathology consultation. Looking forward, a prospective study evaluating outcomes associated with these differences in approach would further inform best practice.
Conclusions
This case series study found the sensitivity and NPV of routine intraoperative evaluation to be 49% and 34%, respectively. Although current guidelines recommend freezing the entire intraoperative specimen, this practice may have little practical utility in improving margin assessment or avoiding adjuvant therapy and may even introduce sampling issues due to intraoperative tissue handling. Given the lack of influence of intraoperative consultation (and driving role of histologically determined ENE) on the need for radiotherapy with or without chemotherapy or second procedure, the practice of routine frozen section intraoperative consultation requires further scrutiny. Future studies comparing TORS with and without intraoperative consultation will better define its utility in SCCUP tumor localization or influence on adjuvant therapies.
Data Sharing Statement
References
- 1.Motz K, Qualliotine JR, Rettig E, Richmon JD, Eisele DW, Fakhry C. Changes in unknown primary squamous cell carcinoma of the head and neck at initial presentation in the era of human papillomavirus. JAMA Otolaryngol Head Neck Surg. 2016;142(3):223-228. doi: 10.1001/jamaoto.2015.3228 [DOI] [PubMed] [Google Scholar]
- 2.Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. a review of diagnostic approaches. Head Neck. 2013;35(1):123-132. doi: 10.1002/hed.21898 [DOI] [PubMed] [Google Scholar]
- 3.Keller LM, Galloway TJ, Holdbrook T, et al. p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck. 2014;36(12):1677-1684. doi: 10.1002/hed.23514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Davis KS, Byrd JK, Mehta V, et al. Occult primary head and neck squamous cell carcinoma: utility of discovering primary lesions. Otolaryngol Head Neck Surg. 2014;151(2):272-278. doi: 10.1177/0194599814533494 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ye W, Arnaud EH, Langerman A, Mannion K, Topf MC. Diagnostic approaches to carcinoma of unknown primary of the head and neck. Eur J Cancer Care (Engl). 2021;30(6):e13459. doi: 10.1111/ecc.13459 [DOI] [PubMed] [Google Scholar]
- 6.Boscolo-Rizzo P, Schroeder L, Romeo S, Pawlita M. The prevalence of human papillomavirus in squamous cell carcinoma of unknown primary site metastatic to neck lymph nodes: a systematic review. Clin Exp Metastasis. 2015;32(8):835-845. doi: 10.1007/s10585-015-9744-z [DOI] [PubMed] [Google Scholar]
- 7.Herruer JM, Taylor SM, MacKay CA, et al. Intraoperative primary tumor identification and margin assessment in head and neck unknown primary tumors. Otolaryngol Head Neck Surg. 2020;162(3):313-318. doi: 10.1177/0194599819900794 [DOI] [PubMed] [Google Scholar]
- 8.Miles BA, Posner MR, Gupta V, et al. De-escalated adjuvant therapy after transoral robotic surgery for human papillomavirus-related oropharyngeal carcinoma: the Sinai robotic surgery (SIRS) trial. Oncologist. 2021;26(6):504-513. doi: 10.1002/onco.13742 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Geltzeiler M, Doerfler S, Turner M, et al. Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: Updates on efficacy, surgical technique and margin status. Oral Oncol. 2017;66:9-13. doi: 10.1016/j.oraloncology.2016.12.033 [DOI] [PubMed] [Google Scholar]
- 10.Durmus K, Rangarajan SV, Old MO, Agrawal A, Teknos TN, Ozer E. Transoral robotic approach to carcinoma of unknown primary. Head Neck. 2014;36(6):848-852. doi: 10.1002/hed.23385 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mehta V, Johnson P, Tassler A, et al. A new paradigm for the diagnosis and management of unknown primary tumors of the head and neck: a role for transoral robotic surgery. Laryngoscope. 2013;123(1):146-151. doi: 10.1002/lary.23562 [DOI] [PubMed] [Google Scholar]
- 12.Ofo E, Spiers H, Kim D, Duvvuri U. Transoral robotic surgery and the unknown primary. ORL J Otorhinolaryngol Relat Spec. 2018;80(3-4):148-155. doi: 10.1159/000490596 [DOI] [PubMed] [Google Scholar]
- 13.Patel SA, Magnuson JS, Holsinger FC, et al. Robotic surgery for primary head and neck squamous cell carcinoma of unknown site. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1203-1211. doi: 10.1001/jamaoto.2013.5189 [DOI] [PubMed] [Google Scholar]
- 14.Ryan JF, Motz KM, Rooper LM, et al. The impact of a stepwise approach to primary tumor detection in squamous cell carcinoma of the neck with unknown primary: unknown primary Detection. Laryngoscope. 2019;129(7):1610-1616. doi: 10.1002/lary.27625 [DOI] [PubMed] [Google Scholar]
- 15.Maghami E, Ismaila N, Alvarez A, et al. Diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck: ASCO Guideline. J Clin Oncol. 2020;38(22):2570-2596. doi: 10.1200/JCO.20.00275 [DOI] [PubMed] [Google Scholar]
- 16.Channir HI, Rubek N, Nielsen HU, et al. Transoral robotic surgery for the management of head and neck squamous cell carcinoma of unknown primary. Acta Otolaryngol. 2015;135(10):1051-1057. doi: 10.3109/00016489.2015.1052983 [DOI] [PubMed] [Google Scholar]
- 17.Du E, Ow TJ, Lo YT, et al. Refining the utility and role of Frozen section in head and neck squamous cell carcinoma resection. Laryngoscope. 2016;126(8):1768-1775. doi: 10.1002/lary.25899 [DOI] [PubMed] [Google Scholar]
- 18.Layfield EM, Schmidt RL, Esebua M, Layfield LJ. Frozen section evaluation of margin status in primary squamous cell carcinomas of the head and neck: a correlation study of frozen section and final diagnoses. Head Neck Pathol. 2018;12(2):175-180. doi: 10.1007/s12105-017-0846-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Tirelli G, Boscolo Nata F, Gatto A, et al. Intraoperative margin control in transoral approach for oral and oropharyngeal cancer: intraoperative margin control. Laryngoscope. 2019;129(8):1810-1815. doi: 10.1002/lary.27567 [DOI] [PubMed] [Google Scholar]
- 20.Berdugo J, Rooper LM, Chiosea SI. RB1, p16, and human papillomavirus in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2021;15(4):1109-1118. doi: 10.1007/s12105-021-01317-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi: 10.3322/caac.21388 [DOI] [PubMed] [Google Scholar]
- 22.van Weert S, Rijken JA, Plantone F, et al. A systematic review on transoral robotic surgery (TORS) for carcinoma of unknown primary origin: Has tongue base mucosectomy become indispensable? Clin Otolaryngol. 2020;45(5):732-738. doi: 10.1111/coa.13565 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Winter SC, Ofo E, Meikle D, et al. Trans-oral robotic assisted tongue base mucosectomy for investigation of cancer of unknown primary in the head and neck region. The UK experience. Clin Otolaryngol. 2017;42(6):1247-1251. doi: 10.1111/coa.12860 [DOI] [PubMed] [Google Scholar]
- 24.Farooq S, Khandavilli S, Dretzke J, et al. Transoral tongue base mucosectomy for the identification of the primary site in the work-up of cancers of unknown origin: Systematic review and meta-analysis. Oral Oncol. 2019;91:97-106. doi: 10.1016/j.oraloncology.2019.02.018 [DOI] [PubMed] [Google Scholar]
- 25.Fu TS, Foreman A, Goldstein DP, de Almeida JR. The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: a systematic review. J Otolaryngol Head Neck Surg. 2016;45(1):28. doi: 10.1186/s40463-016-0142-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Koch WM, Bhatti N, Williams MF, Eisele DW. Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg. 2001;124(3):331-333. doi: 10.1067/mhn.2001.114309 [DOI] [PubMed] [Google Scholar]
- 27.Kothari P, Randhawa PS, Farrell R. Role of tonsillectomy in the search for a squamous cell carcinoma from an unknown primary in the head and neck. Br J Oral Maxillofac Surg. 2008;46(4):283-287. doi: 10.1016/j.bjoms.2007.11.017 [DOI] [PubMed] [Google Scholar]
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