Prognostic impact of incisional or excisional biopsy of cervical lymph node metastases of solid tumors

Prognostic impact of incisional or excisional biopsy of cervical lymph node metastases of solid... Abstract Objectives In performing an open biopsy of a neck mass, an incisional biopsy may increase the risk of cancer cell seeding and dissemination that, ultimately, worsens a patient’s survival. The aim of this study was to compare the impact of incisional and excisional biopsies of cervical lymph node metastases of solid tumors on patients’ survival. Methods A retrospective review was made of patients with cervical metastases of solid tumors who underwent an open biopsy for a diagnosis between 2005 and 2015. Sixty-four patients met the criteria out of 524 open biopsy cases undertaken during the period. Survival analyses were estimated from 33 cases whose initial symptoms were the presence of a neck mass, using two modes of biopsy: excisional and incisional. Results The 2-year overall survival rates in incisional and excisional biopsy groups were 65% and 43%, respectively, and 2-year disease-specific survival rates were 74% and 43%, respectively. The differences were not significant. For lung cancer or head and neck cancer subgroups, survival differences between incisional and excisional biopsy groups were also not significant. Conclusions A carefully targeted physical examination and performing a fine needle aspiration are essential to establish a diagnosis for the etiology of an unknown neck mass. In performing an open biopsy, the effect of an incisional biopsy on patients’ survival was no worse than that of an excisional biopsy, despite the latter being theoretically preferable. cervical metastases, solid tumors, incisional biopsy, excisional biopsy, survival Introduction In the 1950s, Martin and Romieu observed that removal of a neck node for diagnostic purposes lessened the chance of survival (1). Several reports have since demonstrated an obvious adverse effect of violating the neck before definitive surgery (2,3) and therefore a systemic approach to anatomical ‘en block’ removal of neck metastases, namely neck dissection, was developed (4). Consequently, head and neck surgeons carefully searched for a primary lesion in patients with a neck mass of unknown etiology, and, if needed, less invasive pathological examinations of the neck mass, such as fine needle aspiration cytology, were initially considered (5). Sampling a certain amount of tumor from a head and neck lesion is beneficial in order to make a pathological diagnosis of a malignant lymphoma or metastatic tumor that has spread from other organs. Pathologists often request ‘a certain amount’ of tumor in order to perform immunohistochemical staining, flow cytometry or PCR for genetic profiling so as to obtain a proper pathological diagnosis and/or supposed primary organs (6). However, in performing an open biopsy of a neck lymph node, some investigators were concerned that incisional biopsies may increase the risk of cancer cell seeding and dissemination, which would worsen a patient’s survival (3). According to this concept, an excisional biopsy should be performed when a certain amount of cervical lymph node is needed to make a proper diagnosis. However, an excisional biopsy is often hazardous or sometimes impossible when the mass is too large or adheres to adjacent structures. The aim of this study was to investigate the impact of an incisional biopsy compared with an excisional biopsy of cervical lymph node metastases of solid tumors on patients’ survival. Materials and methods Patient data Between January 2005 and December 2015, we undertook 524 open biopsies of cervical lymph nodes for diagnostic purposes. The final pathological results are shown in Table 1. Of these cases, 64 patients with a metastatic solid tumor histologically confirmed by cervical open biopsy were enrolled in this study. The patients consisted of 38 males and 25 females, with an age range of 26–86 years (median age was 62). In seven cases, the biopsy was aimed at the confirmation of distant metastases during the staging of a known primary malignancy. In 16 cases the neck mass recurred in patients with a known past history of malignancy. In eight cases of lung cancer, the cervical mass was clinically presumed to be a metastasis of lung disease and the cervical biopsy was aimed at confirming the presence of lung cancer. In 33 cases, a tumor in the neck was the first manifestation of disease and the primary was consequently searched for after the pathological confirmation of cervical metastases. Primary organs that were proven clinically are shown in Table 2. Eleven cases of carcinomas with an unknown primary (CUP) were found; that is, primary lesions were not identified in any examinations. In this study, patients with squamous cell carcinoma with an unknown primary were classified as part of the head and neck squamous cell carcinoma (HNSCC) group. The ethics committee of Kobe City Medical Center General Hospital approved the study, and informed consent was waived because of the retrospective nature of the study. Table 1. Histological results of 524 cervical lymph node biopsies between 2005 and 2015 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 HNSCC, head and neck squamous cell carcinoma. Table 1. Histological results of 524 cervical lymph node biopsies between 2005 and 2015 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 HNSCC, head and neck squamous cell carcinoma. Table 2. Primary organs of cervical lymph node metastases of solid tumors Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 SCC, squamous cell carcinoma; CUP, carcinoma of unknown origin. Table 2. Primary organs of cervical lymph node metastases of solid tumors Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 SCC, squamous cell carcinoma; CUP, carcinoma of unknown origin. The mode of biopsy The target lymph node was detected using palpitation or by imaging such as computed tomography (CT) or fluorodeoxyglucose positron emission tomography–CT (FDG/PET–CT), and was histologically confirmed after resection. Surgeons performed an open neck biopsy using the following principles: First, one or more palpable and highly movable lymph nodes were chosen and completely removed with an intact capsule (excisional biopsy) under local anesthesia. Second, general anesthesia was applied when the lymph node was not palpable or was behind an important organ, such as the carotid artery. Third, an incisional biopsy was performed only when the lymph node was too large or adhering to adjacent structures or organs and an excisional biopsy was hazardous. The site of biopsy was classified using the American Academy of Otolaryngology–Head and Neck Surgery cervical lymph node level system. Two different modes of biopsy generated two groups: excisional and incisional. Among the 64 patients with a metastatic solid tumor, 48% underwent an incisional biopsy (31/64) and 52% underwent an excisional biopsy (33/64). Survival analysis Survival analyses were estimated using 33 patients for whom a tumor in the neck was the first manifestation of disease. The other sub-analyses were made using an HNSCC group and a lung cancer group. The HNSCC group consisted of 15 patients for whom their disease first manifested as a tumor in the neck; this excluded two patients for whom a neck mass appeared as a recurrent disease. The lung cancer group consisted of 14 patients whose pathological diagnosis was proven by a cervical metastasis, whether a lung tumor was radiologically identified at the time of the biopsy, or not. The survival differences between the mode of biopsy: excisional or incisional was calculated in these three groups. Clinical covariates were dichotomized for statistical evaluation: gender (male vs. female), anesthesia (local vs. general), systemic therapy (yes vs. no), TNM stage (T0–2 vs. T3–4, N1–2 vs. N2b–N3, M0 vs. M1) and a positive p16 immunohistochemical stain in the HNSCC group, treatment modality after biopsy in the HNSCC group (neck dissection, radiation chemotherapy) and clinical stage in the lung cancer group (IIIB vs. IV). The American Joint Committee on Cancer/International Union for Cancer Control (UICC) 7th edition was utilized for TNM classification. Pearson’s chi-square test was used to compare the frequency of the baseline data. Comparisons of age between groups were estimated by Mann–Whitney U tests. The Kaplan–Meier method was used to estimate survival outcomes and the difference in survival was compared using a log-rank test. Excel Tokei 2010 Software for Windows (SSRI, Tokyo, Japan) was used for statistical analysis and a P value of <0.05 was considered to be significant. Results Distribution of level of biopsied lymph nodes according to primary site The distribution of the level of biopsied lymph nodes is shown in Table 3. The most biopsied level was level 5 (posterior cervical triangle) on the left side, followed by level 4 (inferior jugular chain) on the left and level 4 on the right. All lymph node metastases originated from organs below the diaphragm located at level 4 or 5 on the left. In contrast, a majority of the lymph node metastases from HNSCC were located at level 2 (superior jugular chain). Table 3. Distribution of the level of biopsied lymph nodes according to primary organ HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 L, left; R, right; HNSCC, head and neck squamous cell carcinoma; non-SCC, non-squamous cell carcinoma; CUP, carcinoma of unknown origin; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Table 3. Distribution of the level of biopsied lymph nodes according to primary organ HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 L, left; R, right; HNSCC, head and neck squamous cell carcinoma; non-SCC, non-squamous cell carcinoma; CUP, carcinoma of unknown origin; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Clinical features according to the mode of biopsy Table 4 shows the association between the mode of biopsy and clinical covariates among 33 patients whose tumor in the neck was the first manifestation of disease. None of the clinical covariates differed significantly between the groups. Table 5 shows the association between the mode of biopsy and clinical covariates in the HNSCC group. Anesthesia method and nodal stage demonstrated a significant difference between groups; general anesthesia was chosen more frequently in an excisional biopsy and the nodal stage was more likely to be advanced in an incisional biopsy. Table 4. Relationship between mode of biopsy, clinical features and post-treatments of 33 patients whose tumor in the neck was the first manifestation of disease Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 HNSCC, head and neck squamous cell carcinoma; CUP, carcinoma of unknown origin; non-SCC, non-squamous cell carcinoma; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Table 4. Relationship between mode of biopsy, clinical features and post-treatments of 33 patients whose tumor in the neck was the first manifestation of disease Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 HNSCC, head and neck squamous cell carcinoma; CUP, carcinoma of unknown origin; non-SCC, non-squamous cell carcinoma; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Table 5. Relationship between mode of biopsy, clinical covariates and post-treatments of 15 patients with HNSCCs Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 CUP, carcinoma of unknown origin; HNSCC, head and neck squamous cell carcinoma; UICC 7th: International Union for Cancer Control 7th edition; IHC, immunohistochemical; N/A, not applicable. Table 5. Relationship between mode of biopsy, clinical covariates and post-treatments of 15 patients with HNSCCs Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 CUP, carcinoma of unknown origin; HNSCC, head and neck squamous cell carcinoma; UICC 7th: International Union for Cancer Control 7th edition; IHC, immunohistochemical; N/A, not applicable. Table 6 shows the association between the mode of biopsy and clinical covariates in the lung cancer group. None of the clinical covariates differed significantly between the groups. Table 6. Relationship between mode of biopsy, clinical covariates and post-treatments of 14 patients with lung cancers Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 UICC 7th, International Union for Cancer Control 7th edition; BSC, best supportive care; N/A, not applicable. Table 6. Relationship between mode of biopsy, clinical covariates and post-treatments of 14 patients with lung cancers Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 UICC 7th, International Union for Cancer Control 7th edition; BSC, best supportive care; N/A, not applicable. Survival The median time to death or last follow-up of 33 patients whose tumor in the neck was the first manifestation of disease was 762 days. Fourteen deaths occurred because of the disease and one death was due to another cause. The 2-year overall survival (OS) rates in incisional and excisional biopsy groups were 65% and 43%, respectively, and 2-year disease-specific survival (DSS) rates were 74% and 43%, respectively (Fig. 1). Patients in the incisional biopsy group showed better survival in terms of OS and DSS, although differences were not significant. Figure 1. View largeDownload slide Comparison between patients whose tumor in the neck was the first manifestation of the disease with an incisional or excisional biopsy in terms of overall survival (OS) (a) and disease-specific survival (DSS) (b) according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.25) or DSS (P = 0.10). Figure 1. View largeDownload slide Comparison between patients whose tumor in the neck was the first manifestation of the disease with an incisional or excisional biopsy in terms of overall survival (OS) (a) and disease-specific survival (DSS) (b) according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.25) or DSS (P = 0.10). The median time to death or last follow-up for the HNSCC group was 1473 days. Two deaths occurred due to the disease and no death from other causes. The 3-year OS and DSS rates in the incisional and excisional biopsy groups were 89% and 80%, respectively (Fig. 2). Patients in both biopsy groups showed similar survival curves, despite an advanced nodal stage being significantly associated with the incisional biopsy group. Figure 2. View largeDownload slide Comparison between head and neck squamous cell carcinoma (HNSCC) cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. OS and DSS showed the same survival curves because death from other causes did not exist in this group. Significance was based on log-rank comparisons. Significant differences were not observed in OS = DSS (P = 0.61). Figure 2. View largeDownload slide Comparison between head and neck squamous cell carcinoma (HNSCC) cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. OS and DSS showed the same survival curves because death from other causes did not exist in this group. Significance was based on log-rank comparisons. Significant differences were not observed in OS = DSS (P = 0.61). The median time to death or last follow-up of lung cancer was 398.5 days. Ten deaths occurred due to the disease and one death due to another cause. The 2-year OS rates in the incisional and excisional biopsy groups were 17% and 25%, respectively, and the 2-year DSS rates were 20% and 25%, respectively (Fig. 3). Patients in both biopsy groups showed similar survival curves. Figure 3. View largeDownload slide Comparison between lung cancer cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.69) or DSS (P = 0.92). Figure 3. View largeDownload slide Comparison between lung cancer cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.69) or DSS (P = 0.92). Discussion In this study, we came across 64 cases with cervical metastatic solid tumors, which were much less frequent than the 318 cases with hematologic malignancies during the period. As described in the ‘Clinical Practice Guideline: Evaluation of the Neck Mass in Adults’, we ordinarily perform a targeted physical examination, including visualizing the mucosa of the larynx, base of tongue and pharynx, as well as a fine needle aspiration (FNA) instead of an open biopsy for patients with a neck mass (5). Open biopsies were planned for patients suspected of having a malignant lymphoma or patients without a diagnosis or primary site that could be identified by endoscopic examination, imaging and/or FNA. HNSCC (17 cases, 27%) and lung cancer (17 cases, 27%) were identified as making up the majority of primary organs, while organs below the diaphragm made up more than a quarter (18 cases, 28%). In this study, all cases with a cervical metastasis from organs below the diaphragm occurred at level 4 or 5 on the left. Further examinations should be undertaken, such as abdominal CT/PET–CT or ultrasonography, and/or with a large intestinal fiberscope, in routine workups to detect the primary site when a mass is evaluated in the left lower neck. Concerning the prognosis, we had expected a worse prognosis for patients who received an incisional biopsy compared with those who underwent an excisional biopsy since incisional biopsies are thought to increase the risk of cancer cell seeding and dissemination (3). In addition, the surgeon may prefer an incisional biopsy for patients with a larger, and/or fixed neck mass, indicating a more advanced condition of metastasis. In the present study, nodal stage in the HNSCC group was significantly advanced in the incisional biopsy group compared to the excisional biopsy group. However, of 33 patients whose tumor in the neck was the first manifestation of disease, those who received an incisional biopsy demonstrated a better prognosis, although this was not significant, than those who received an excisional biopsy in this study. We presumed the reason for this observation is that the existence of neck metastases, which is defined as a distant metastasis unless the primary site exists in a head and neck lesion or in the lung, has a much greater influence on patients’ survival than the mode of the biopsy. This was why we evaluated survival in two more subgroups, the lung cancer and HNSCC groups. As a result, a significant survival disadvantage for an incisional biopsy could not be shown in either the lung cancer or the HNSCC group. Dong et al. examined the influence of an incisional biopsy of supraclavicular lymph node metastases by lung cancer in 202 cases with Stage IIIB or Stage IV non-small cell lung cancer (7). They reported that significant differences, in terms of overall survival, were not observed between cases with an incisional or excisional biopsy, despite patients with an incisional biopsy having larger and more fixed lymph nodes. The present study is compatible with the findings of the Dong et al. report. Moreover, as for lung cancer, recent progress in the use of tyrosine kinase and/or immune check point inhibitors has significantly improved patients’ survival especially for Stage III and IV cancer. In fact, we have now followed the progress of a patient with Stage IV lung cancer who received an incisional biopsy and has survived for more than 4 years with no evidence of disease after treatment with an ALK (anaplastic lymphoma kinase) inhibitor. This suggested that chemotherapeutic agents may cancel the adverse effects of an incisional biopsy. In cases with HNSCC, the finding that an incisional biopsy did not adversely influence patients’ survival was unexpected. This is because it is a long-time axiom of head and neck surgery that an incisional biopsy of lymph nodes in HNSCC, which disrupts the lymphatic membrane, would ‘violate’ the neck and predispose the patient to loco-regional and distant recurrence, resulting in a worse prognosis (1–3). However, the 3-year survival rates in the incisional and excisional biopsy groups were 89% and 80%, respectively. We highlight two reasons to explain why patients who underwent an incisional biopsy had a more favorable prognosis than expected. Initially, radiotherapy and/or chemotherapy was undertaken by 93% of patients (14 out of 15) after an open biopsy. Ellis et al. analyzed 508 patients with HNSCC and positive neck nodes who had been treated with radiotherapy. They showed that an open biopsy did not have a detrimental effect on loco-regional control, distant metastasis and disease-specific survival (8). They concluded that a potential adverse effect of ‘violating the neck’ cannot be demonstrated if appropriate management, such as radiotherapy, is subsequently performed. Second, 8 out of 13 patients with oropharyngeal cancer or CUP (61%) were shown to be p16 positive, a surrogate maker of human papillomavirus (HPV), while only three patients turned out to be negative in our series of HNSCC cases. Recently, in Japan, more than half of cases of oropharyngeal SCC were reported to be HPV positive (9–11). As for patients with SCC and an unknown primary, almost 70% were reported to be p16 positive (12,13). Loyo et al. reviewed 53 patients who had undergone an open cervical biopsy for a diagnosis prior to definitive therapy and reported that 87% were found to be HPV positive (14). As is well known, HPV-related SCC shows a better response to radiotherapy and/or chemotherapy and a subsequently favorable survival (15,16). Moreover, Zenga et al. reported that an open biopsy in cases with HPV-related SCC did not have an adverse effect on patients’ favorable overall, disease-specific or disease-free survival in their series of 45 patients with HPV positive oropharyngeal SCC (17). In conclusion, a carefully targeted physical examination, including visualizing the mucosa of the larynx, base of tongue and pharynx, and performing a FNA is essential to establish a diagnosis for the etiology of an unknown neck mass. In performing an open biopsy, an incisional neck biopsy does not show a worse effect on patients’ survival than an excisional biopsy, even though an excisional biopsy is theoretically preferable. Funding This work was supported by the Kasahara Fund for the Promotion of Cancer Research. Conflict of interest statement The authors report no conflicts of interest in this work. References 1 Martin H , Romieu C . The diagnostic significance of a lump in the neck . Postgrad Med 1952 ; 11 : 491 – 500 . Google Scholar CrossRef Search ADS PubMed 2 Shaw HJ . Metastatic carcinoma in cervical lymph nodes with occult primary tumour – diagnosis and treatment . J Laryngol Otol 1970 ; 84 : 249 – 65 . Google Scholar CrossRef Search ADS PubMed 3 McGuirt WF , McCabe BF . Significance of node biopsy before definitive treatment of cervical metastatic carcinoma . Laryngoscope 1978 ; 88 : 594 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Martin H , Del Valle B , Ehrlich H , et al. . Neck dissection . Cancer 1951 ; 4 : 441 – 99 . Google Scholar CrossRef Search ADS PubMed 5 Pynnonen MA , Gillespie MB , Roman B , et al. . Clinical practice guideline: evaluation of the neck mass in adults executive summary . Otolaryngol Head Neck Surg 2017 ; 157 : 355 – 71 . Google Scholar CrossRef Search ADS PubMed 6 NCCN Clinical Practise Guideline in Oncology . B-Cell Lymphoma. Version2. 2018 . http://www.nccn.org. 7 Dong S , Zhao N , Deng W , et al. . Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study . World J Surg Oncol 2017 ; 15 : 12 . Google Scholar CrossRef Search ADS PubMed 8 Ellis ER , Mendenhall WM , Rao PV , et al. . Incisional or excisional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection . Head Neck 1991 ; 13 : 177 – 83 . Google Scholar CrossRef Search ADS PubMed 9 Hama T , Tokumaru Y , Fujii M , et al. . Prevalence of human papillomavirus in oropharyngeal cancer: a multicenter study in Japan . Oncology 2014 ; 87 : 173 – 82 . Google Scholar CrossRef Search ADS PubMed 10 Saito Y , Yoshida M , Omura G , et al. . Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma . Jpn J Clin Oncol 2015 ; 45 : 828 – 36 . Google Scholar CrossRef Search ADS PubMed 11 Shinohara S , Kikuchi M , Tona R , et al. . Prognostic impact of p16 and p53 expression in oropharyngeal squamous cell carcinomas . Jpn J Clin Oncol 2014 ; 44 : 232 – 40 . Google Scholar CrossRef Search ADS PubMed 12 Dixon PR , Au M , Hosni A , et al. . Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma . Head Neck 2016 ; 38 : 1347 – 53 . Google Scholar CrossRef Search ADS PubMed 13 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 : 1677 – 84 . Google Scholar CrossRef Search ADS PubMed 14 Loyo M , Johnson JT , Westra WH , et al. . Management of the ‘violated neck’ in the era of chemoradiation . Laryngoscope 2011 ; 121 : 2349 – 58 . Google Scholar CrossRef Search ADS PubMed 15 Allen CT , Lewis JS Jr. , El-Mofty SK , et al. . Human papillomavirus and oropharynx cancer: biology, detection and clinical implications . Laryngoscope 2010 ; 120 : 1756 – 72 . Google Scholar CrossRef Search ADS PubMed 16 Ang KK , Harris J , Wheeler R , et al. . Human papillomavirus and survival of patients with oropharyngeal cancer . N Engl J Med 2010 ; 363 : 24 – 35 . Google Scholar CrossRef Search ADS PubMed 17 Zenga J , Graboyes EM , Haughey BH , et al. . Definitive surgical therapy after open neck biopsy for HPV-related oropharyngeal cancer . Otolaryngol Head Neck Surg 2016 ; 154 : 657 – 66 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 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Prognostic impact of incisional or excisional biopsy of cervical lymph node metastases of solid tumors

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Abstract

Abstract Objectives In performing an open biopsy of a neck mass, an incisional biopsy may increase the risk of cancer cell seeding and dissemination that, ultimately, worsens a patient’s survival. The aim of this study was to compare the impact of incisional and excisional biopsies of cervical lymph node metastases of solid tumors on patients’ survival. Methods A retrospective review was made of patients with cervical metastases of solid tumors who underwent an open biopsy for a diagnosis between 2005 and 2015. Sixty-four patients met the criteria out of 524 open biopsy cases undertaken during the period. Survival analyses were estimated from 33 cases whose initial symptoms were the presence of a neck mass, using two modes of biopsy: excisional and incisional. Results The 2-year overall survival rates in incisional and excisional biopsy groups were 65% and 43%, respectively, and 2-year disease-specific survival rates were 74% and 43%, respectively. The differences were not significant. For lung cancer or head and neck cancer subgroups, survival differences between incisional and excisional biopsy groups were also not significant. Conclusions A carefully targeted physical examination and performing a fine needle aspiration are essential to establish a diagnosis for the etiology of an unknown neck mass. In performing an open biopsy, the effect of an incisional biopsy on patients’ survival was no worse than that of an excisional biopsy, despite the latter being theoretically preferable. cervical metastases, solid tumors, incisional biopsy, excisional biopsy, survival Introduction In the 1950s, Martin and Romieu observed that removal of a neck node for diagnostic purposes lessened the chance of survival (1). Several reports have since demonstrated an obvious adverse effect of violating the neck before definitive surgery (2,3) and therefore a systemic approach to anatomical ‘en block’ removal of neck metastases, namely neck dissection, was developed (4). Consequently, head and neck surgeons carefully searched for a primary lesion in patients with a neck mass of unknown etiology, and, if needed, less invasive pathological examinations of the neck mass, such as fine needle aspiration cytology, were initially considered (5). Sampling a certain amount of tumor from a head and neck lesion is beneficial in order to make a pathological diagnosis of a malignant lymphoma or metastatic tumor that has spread from other organs. Pathologists often request ‘a certain amount’ of tumor in order to perform immunohistochemical staining, flow cytometry or PCR for genetic profiling so as to obtain a proper pathological diagnosis and/or supposed primary organs (6). However, in performing an open biopsy of a neck lymph node, some investigators were concerned that incisional biopsies may increase the risk of cancer cell seeding and dissemination, which would worsen a patient’s survival (3). According to this concept, an excisional biopsy should be performed when a certain amount of cervical lymph node is needed to make a proper diagnosis. However, an excisional biopsy is often hazardous or sometimes impossible when the mass is too large or adheres to adjacent structures. The aim of this study was to investigate the impact of an incisional biopsy compared with an excisional biopsy of cervical lymph node metastases of solid tumors on patients’ survival. Materials and methods Patient data Between January 2005 and December 2015, we undertook 524 open biopsies of cervical lymph nodes for diagnostic purposes. The final pathological results are shown in Table 1. Of these cases, 64 patients with a metastatic solid tumor histologically confirmed by cervical open biopsy were enrolled in this study. The patients consisted of 38 males and 25 females, with an age range of 26–86 years (median age was 62). In seven cases, the biopsy was aimed at the confirmation of distant metastases during the staging of a known primary malignancy. In 16 cases the neck mass recurred in patients with a known past history of malignancy. In eight cases of lung cancer, the cervical mass was clinically presumed to be a metastasis of lung disease and the cervical biopsy was aimed at confirming the presence of lung cancer. In 33 cases, a tumor in the neck was the first manifestation of disease and the primary was consequently searched for after the pathological confirmation of cervical metastases. Primary organs that were proven clinically are shown in Table 2. Eleven cases of carcinomas with an unknown primary (CUP) were found; that is, primary lesions were not identified in any examinations. In this study, patients with squamous cell carcinoma with an unknown primary were classified as part of the head and neck squamous cell carcinoma (HNSCC) group. The ethics committee of Kobe City Medical Center General Hospital approved the study, and informed consent was waived because of the retrospective nature of the study. Table 1. Histological results of 524 cervical lymph node biopsies between 2005 and 2015 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 HNSCC, head and neck squamous cell carcinoma. Table 1. Histological results of 524 cervical lymph node biopsies between 2005 and 2015 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 Hematologic malignancy 318  Malignant lymphoma 315  Leukemia 3 Metastatic solid tumor 64  HNSCC 17  Lung cancer 17  Others 30 Infectious granulomatous lymphadenitis 34  Tuberculosis 31  Toxoplasma 3 Noninfectious granulomatous lymphadenitis 15  Sarcoidosis 10  Unknown 5 Infectious lymphadenitis 12 Other causes 25  Kikuchi disease 14  IgG4-related disease 7  Castleman disease 3  Rosai–Dorfman disease 1  Reactive lymphadenitis 56 Total 524 HNSCC, head and neck squamous cell carcinoma. Table 2. Primary organs of cervical lymph node metastases of solid tumors Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 SCC, squamous cell carcinoma; CUP, carcinoma of unknown origin. Table 2. Primary organs of cervical lymph node metastases of solid tumors Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 Head and neck SCC 17  Oropharynx 8  CUP 5  Nasopharynx 1  Maxilla 1  Hypopharynx 1  Larynx 1 Lung 17 CUP (non-SCC) 6  Adenocarcinoma 4  Mucoepidermoid carcinoma 2 Upper gastrointestinal 3  Esophagus 2  Stomach 1 Lower gastrointestinal 3  Colon 3 Hepatobiliary and pancreatic 4  Pancreas 3  Liver 1 Gynecologic 6  Cervix 2  Uterine body 2  Ovary 2 Urologic 4  Kidney 3  Ureter 1 Others 2  Breast 1  Thyroid 1 Sarcoma 2  Olfactory neuroblastoma 1  Angiosarcoma 1 Total 64 SCC, squamous cell carcinoma; CUP, carcinoma of unknown origin. The mode of biopsy The target lymph node was detected using palpitation or by imaging such as computed tomography (CT) or fluorodeoxyglucose positron emission tomography–CT (FDG/PET–CT), and was histologically confirmed after resection. Surgeons performed an open neck biopsy using the following principles: First, one or more palpable and highly movable lymph nodes were chosen and completely removed with an intact capsule (excisional biopsy) under local anesthesia. Second, general anesthesia was applied when the lymph node was not palpable or was behind an important organ, such as the carotid artery. Third, an incisional biopsy was performed only when the lymph node was too large or adhering to adjacent structures or organs and an excisional biopsy was hazardous. The site of biopsy was classified using the American Academy of Otolaryngology–Head and Neck Surgery cervical lymph node level system. Two different modes of biopsy generated two groups: excisional and incisional. Among the 64 patients with a metastatic solid tumor, 48% underwent an incisional biopsy (31/64) and 52% underwent an excisional biopsy (33/64). Survival analysis Survival analyses were estimated using 33 patients for whom a tumor in the neck was the first manifestation of disease. The other sub-analyses were made using an HNSCC group and a lung cancer group. The HNSCC group consisted of 15 patients for whom their disease first manifested as a tumor in the neck; this excluded two patients for whom a neck mass appeared as a recurrent disease. The lung cancer group consisted of 14 patients whose pathological diagnosis was proven by a cervical metastasis, whether a lung tumor was radiologically identified at the time of the biopsy, or not. The survival differences between the mode of biopsy: excisional or incisional was calculated in these three groups. Clinical covariates were dichotomized for statistical evaluation: gender (male vs. female), anesthesia (local vs. general), systemic therapy (yes vs. no), TNM stage (T0–2 vs. T3–4, N1–2 vs. N2b–N3, M0 vs. M1) and a positive p16 immunohistochemical stain in the HNSCC group, treatment modality after biopsy in the HNSCC group (neck dissection, radiation chemotherapy) and clinical stage in the lung cancer group (IIIB vs. IV). The American Joint Committee on Cancer/International Union for Cancer Control (UICC) 7th edition was utilized for TNM classification. Pearson’s chi-square test was used to compare the frequency of the baseline data. Comparisons of age between groups were estimated by Mann–Whitney U tests. The Kaplan–Meier method was used to estimate survival outcomes and the difference in survival was compared using a log-rank test. Excel Tokei 2010 Software for Windows (SSRI, Tokyo, Japan) was used for statistical analysis and a P value of <0.05 was considered to be significant. Results Distribution of level of biopsied lymph nodes according to primary site The distribution of the level of biopsied lymph nodes is shown in Table 3. The most biopsied level was level 5 (posterior cervical triangle) on the left side, followed by level 4 (inferior jugular chain) on the left and level 4 on the right. All lymph node metastases originated from organs below the diaphragm located at level 4 or 5 on the left. In contrast, a majority of the lymph node metastases from HNSCC were located at level 2 (superior jugular chain). Table 3. Distribution of the level of biopsied lymph nodes according to primary organ HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 L, left; R, right; HNSCC, head and neck squamous cell carcinoma; non-SCC, non-squamous cell carcinoma; CUP, carcinoma of unknown origin; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Table 3. Distribution of the level of biopsied lymph nodes according to primary organ HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 HNSCC Lung CUP non-SCC Upper GI Lower GI HBP Gyne Uro Others Total L2 6 1 7 L3 1 1 L4 1 4 2 3 1 2 1 14 L5 3 1 3 2 3 1 5 2 20 R2 4 1 5 R3 2 1 1 4 R4 7 1 1 9 R5 4 4 Total 17 17 6 3 3 4 6 4 4 64 L, left; R, right; HNSCC, head and neck squamous cell carcinoma; non-SCC, non-squamous cell carcinoma; CUP, carcinoma of unknown origin; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Clinical features according to the mode of biopsy Table 4 shows the association between the mode of biopsy and clinical covariates among 33 patients whose tumor in the neck was the first manifestation of disease. None of the clinical covariates differed significantly between the groups. Table 5 shows the association between the mode of biopsy and clinical covariates in the HNSCC group. Anesthesia method and nodal stage demonstrated a significant difference between groups; general anesthesia was chosen more frequently in an excisional biopsy and the nodal stage was more likely to be advanced in an incisional biopsy. Table 4. Relationship between mode of biopsy, clinical features and post-treatments of 33 patients whose tumor in the neck was the first manifestation of disease Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 HNSCC, head and neck squamous cell carcinoma; CUP, carcinoma of unknown origin; non-SCC, non-squamous cell carcinoma; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Table 4. Relationship between mode of biopsy, clinical features and post-treatments of 33 patients whose tumor in the neck was the first manifestation of disease Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 Incisional Excisional P value Total 19 14 Gender  Male 11 8 0.97  Female 8 6 Age 62 (26–76) 62 (49–86) 0.55 Primary site  HNSCC 10 5  Lung 4 2    CUP non-SCC 3 3    Upper GI 1 0    Lower GI 0 1    HBP 0 1    Gyne 0 1    Uro 1 0    Others 0 1   Anesthesia  General 2 5 0.08  Local 17 9 Treatment after biopsy  Systemic treatment 18 12 0.37  Supportive care only 1 2 HNSCC, head and neck squamous cell carcinoma; CUP, carcinoma of unknown origin; non-SCC, non-squamous cell carcinoma; GI, gastrointestinal tract; HBP, hepatobiliary and pancreatic; Gyne, gynecologic; Uro, urologic. Table 5. Relationship between mode of biopsy, clinical covariates and post-treatments of 15 patients with HNSCCs Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 CUP, carcinoma of unknown origin; HNSCC, head and neck squamous cell carcinoma; UICC 7th: International Union for Cancer Control 7th edition; IHC, immunohistochemical; N/A, not applicable. Table 5. Relationship between mode of biopsy, clinical covariates and post-treatments of 15 patients with HNSCCs Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 Incisional Excisional P value Total 10 5 Gender  Male 7 4 0.68  Female 3 1 Age 61 (35–76) 60 (49–70) 1.0 Primary site  Oropharynx 5 3  CUP 3 2  Nasopharynx 1 0  Hypopharynx 1 0 Anesthesia  General 1 4 <0.01  Local 9 1 T stage (UICC 7th)  T0–T2 10 5 N/A  T3–T4 0 0 N stage (UICC 7th)  N1–N2a 2 4 0.03  N2b–N3 8 1 M stage (UICC 7th)  M0 9 5 0.46  M1 1 0 p16 IHC staining  Positive 6 2 0.78  Negative 2 1  N/A 2 2 Treatment after biopsy  Neck dissection 7 2 0.26  Radiation 9 5 0.46  Chemotherapy 9 5 0.46 CUP, carcinoma of unknown origin; HNSCC, head and neck squamous cell carcinoma; UICC 7th: International Union for Cancer Control 7th edition; IHC, immunohistochemical; N/A, not applicable. Table 6 shows the association between the mode of biopsy and clinical covariates in the lung cancer group. None of the clinical covariates differed significantly between the groups. Table 6. Relationship between mode of biopsy, clinical covariates and post-treatments of 14 patients with lung cancers Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 UICC 7th, International Union for Cancer Control 7th edition; BSC, best supportive care; N/A, not applicable. Table 6. Relationship between mode of biopsy, clinical covariates and post-treatments of 14 patients with lung cancers Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 Incisional Excisional P value Total 6 8 Gender  Male 5 3 0.08  Female 1 5 Age 68 (47–79) 66 (38–86) 0.90 Anesthesia  General 0 0 N/A  Local 6 8 Histology  Adenocarcinoma 3 5  Small cell carcinoma 1 2  Squamous cell carcinoma 2 0  Large cell carcinoma 0 1 Stage (UICC 7th)  IIIB 1 3 0.39  IV 5 5 Treatment after biopsy  Chemotherapy 4 6 0.73  Untreated (BSC) 2 2 UICC 7th, International Union for Cancer Control 7th edition; BSC, best supportive care; N/A, not applicable. Survival The median time to death or last follow-up of 33 patients whose tumor in the neck was the first manifestation of disease was 762 days. Fourteen deaths occurred because of the disease and one death was due to another cause. The 2-year overall survival (OS) rates in incisional and excisional biopsy groups were 65% and 43%, respectively, and 2-year disease-specific survival (DSS) rates were 74% and 43%, respectively (Fig. 1). Patients in the incisional biopsy group showed better survival in terms of OS and DSS, although differences were not significant. Figure 1. View largeDownload slide Comparison between patients whose tumor in the neck was the first manifestation of the disease with an incisional or excisional biopsy in terms of overall survival (OS) (a) and disease-specific survival (DSS) (b) according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.25) or DSS (P = 0.10). Figure 1. View largeDownload slide Comparison between patients whose tumor in the neck was the first manifestation of the disease with an incisional or excisional biopsy in terms of overall survival (OS) (a) and disease-specific survival (DSS) (b) according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.25) or DSS (P = 0.10). The median time to death or last follow-up for the HNSCC group was 1473 days. Two deaths occurred due to the disease and no death from other causes. The 3-year OS and DSS rates in the incisional and excisional biopsy groups were 89% and 80%, respectively (Fig. 2). Patients in both biopsy groups showed similar survival curves, despite an advanced nodal stage being significantly associated with the incisional biopsy group. Figure 2. View largeDownload slide Comparison between head and neck squamous cell carcinoma (HNSCC) cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. OS and DSS showed the same survival curves because death from other causes did not exist in this group. Significance was based on log-rank comparisons. Significant differences were not observed in OS = DSS (P = 0.61). Figure 2. View largeDownload slide Comparison between head and neck squamous cell carcinoma (HNSCC) cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. OS and DSS showed the same survival curves because death from other causes did not exist in this group. Significance was based on log-rank comparisons. Significant differences were not observed in OS = DSS (P = 0.61). The median time to death or last follow-up of lung cancer was 398.5 days. Ten deaths occurred due to the disease and one death due to another cause. The 2-year OS rates in the incisional and excisional biopsy groups were 17% and 25%, respectively, and the 2-year DSS rates were 20% and 25%, respectively (Fig. 3). Patients in both biopsy groups showed similar survival curves. Figure 3. View largeDownload slide Comparison between lung cancer cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.69) or DSS (P = 0.92). Figure 3. View largeDownload slide Comparison between lung cancer cases with an incisional or excisional biopsy in terms of OS and DSS according to the Kaplan–Meier method. Significance was based on log-rank comparisons. Significant differences were not observed in OS (P = 0.69) or DSS (P = 0.92). Discussion In this study, we came across 64 cases with cervical metastatic solid tumors, which were much less frequent than the 318 cases with hematologic malignancies during the period. As described in the ‘Clinical Practice Guideline: Evaluation of the Neck Mass in Adults’, we ordinarily perform a targeted physical examination, including visualizing the mucosa of the larynx, base of tongue and pharynx, as well as a fine needle aspiration (FNA) instead of an open biopsy for patients with a neck mass (5). Open biopsies were planned for patients suspected of having a malignant lymphoma or patients without a diagnosis or primary site that could be identified by endoscopic examination, imaging and/or FNA. HNSCC (17 cases, 27%) and lung cancer (17 cases, 27%) were identified as making up the majority of primary organs, while organs below the diaphragm made up more than a quarter (18 cases, 28%). In this study, all cases with a cervical metastasis from organs below the diaphragm occurred at level 4 or 5 on the left. Further examinations should be undertaken, such as abdominal CT/PET–CT or ultrasonography, and/or with a large intestinal fiberscope, in routine workups to detect the primary site when a mass is evaluated in the left lower neck. Concerning the prognosis, we had expected a worse prognosis for patients who received an incisional biopsy compared with those who underwent an excisional biopsy since incisional biopsies are thought to increase the risk of cancer cell seeding and dissemination (3). In addition, the surgeon may prefer an incisional biopsy for patients with a larger, and/or fixed neck mass, indicating a more advanced condition of metastasis. In the present study, nodal stage in the HNSCC group was significantly advanced in the incisional biopsy group compared to the excisional biopsy group. However, of 33 patients whose tumor in the neck was the first manifestation of disease, those who received an incisional biopsy demonstrated a better prognosis, although this was not significant, than those who received an excisional biopsy in this study. We presumed the reason for this observation is that the existence of neck metastases, which is defined as a distant metastasis unless the primary site exists in a head and neck lesion or in the lung, has a much greater influence on patients’ survival than the mode of the biopsy. This was why we evaluated survival in two more subgroups, the lung cancer and HNSCC groups. As a result, a significant survival disadvantage for an incisional biopsy could not be shown in either the lung cancer or the HNSCC group. Dong et al. examined the influence of an incisional biopsy of supraclavicular lymph node metastases by lung cancer in 202 cases with Stage IIIB or Stage IV non-small cell lung cancer (7). They reported that significant differences, in terms of overall survival, were not observed between cases with an incisional or excisional biopsy, despite patients with an incisional biopsy having larger and more fixed lymph nodes. The present study is compatible with the findings of the Dong et al. report. Moreover, as for lung cancer, recent progress in the use of tyrosine kinase and/or immune check point inhibitors has significantly improved patients’ survival especially for Stage III and IV cancer. In fact, we have now followed the progress of a patient with Stage IV lung cancer who received an incisional biopsy and has survived for more than 4 years with no evidence of disease after treatment with an ALK (anaplastic lymphoma kinase) inhibitor. This suggested that chemotherapeutic agents may cancel the adverse effects of an incisional biopsy. In cases with HNSCC, the finding that an incisional biopsy did not adversely influence patients’ survival was unexpected. This is because it is a long-time axiom of head and neck surgery that an incisional biopsy of lymph nodes in HNSCC, which disrupts the lymphatic membrane, would ‘violate’ the neck and predispose the patient to loco-regional and distant recurrence, resulting in a worse prognosis (1–3). However, the 3-year survival rates in the incisional and excisional biopsy groups were 89% and 80%, respectively. We highlight two reasons to explain why patients who underwent an incisional biopsy had a more favorable prognosis than expected. Initially, radiotherapy and/or chemotherapy was undertaken by 93% of patients (14 out of 15) after an open biopsy. Ellis et al. analyzed 508 patients with HNSCC and positive neck nodes who had been treated with radiotherapy. They showed that an open biopsy did not have a detrimental effect on loco-regional control, distant metastasis and disease-specific survival (8). They concluded that a potential adverse effect of ‘violating the neck’ cannot be demonstrated if appropriate management, such as radiotherapy, is subsequently performed. Second, 8 out of 13 patients with oropharyngeal cancer or CUP (61%) were shown to be p16 positive, a surrogate maker of human papillomavirus (HPV), while only three patients turned out to be negative in our series of HNSCC cases. Recently, in Japan, more than half of cases of oropharyngeal SCC were reported to be HPV positive (9–11). As for patients with SCC and an unknown primary, almost 70% were reported to be p16 positive (12,13). Loyo et al. reviewed 53 patients who had undergone an open cervical biopsy for a diagnosis prior to definitive therapy and reported that 87% were found to be HPV positive (14). As is well known, HPV-related SCC shows a better response to radiotherapy and/or chemotherapy and a subsequently favorable survival (15,16). Moreover, Zenga et al. reported that an open biopsy in cases with HPV-related SCC did not have an adverse effect on patients’ favorable overall, disease-specific or disease-free survival in their series of 45 patients with HPV positive oropharyngeal SCC (17). In conclusion, a carefully targeted physical examination, including visualizing the mucosa of the larynx, base of tongue and pharynx, and performing a FNA is essential to establish a diagnosis for the etiology of an unknown neck mass. In performing an open biopsy, an incisional neck biopsy does not show a worse effect on patients’ survival than an excisional biopsy, even though an excisional biopsy is theoretically preferable. Funding This work was supported by the Kasahara Fund for the Promotion of Cancer Research. Conflict of interest statement The authors report no conflicts of interest in this work. References 1 Martin H , Romieu C . The diagnostic significance of a lump in the neck . Postgrad Med 1952 ; 11 : 491 – 500 . Google Scholar CrossRef Search ADS PubMed 2 Shaw HJ . Metastatic carcinoma in cervical lymph nodes with occult primary tumour – diagnosis and treatment . J Laryngol Otol 1970 ; 84 : 249 – 65 . Google Scholar CrossRef Search ADS PubMed 3 McGuirt WF , McCabe BF . Significance of node biopsy before definitive treatment of cervical metastatic carcinoma . Laryngoscope 1978 ; 88 : 594 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Martin H , Del Valle B , Ehrlich H , et al. . Neck dissection . Cancer 1951 ; 4 : 441 – 99 . Google Scholar CrossRef Search ADS PubMed 5 Pynnonen MA , Gillespie MB , Roman B , et al. . Clinical practice guideline: evaluation of the neck mass in adults executive summary . Otolaryngol Head Neck Surg 2017 ; 157 : 355 – 71 . Google Scholar CrossRef Search ADS PubMed 6 NCCN Clinical Practise Guideline in Oncology . B-Cell Lymphoma. Version2. 2018 . http://www.nccn.org. 7 Dong S , Zhao N , Deng W , et al. . Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study . World J Surg Oncol 2017 ; 15 : 12 . Google Scholar CrossRef Search ADS PubMed 8 Ellis ER , Mendenhall WM , Rao PV , et al. . Incisional or excisional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection . Head Neck 1991 ; 13 : 177 – 83 . Google Scholar CrossRef Search ADS PubMed 9 Hama T , Tokumaru Y , Fujii M , et al. . Prevalence of human papillomavirus in oropharyngeal cancer: a multicenter study in Japan . Oncology 2014 ; 87 : 173 – 82 . Google Scholar CrossRef Search ADS PubMed 10 Saito Y , Yoshida M , Omura G , et al. . Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma . Jpn J Clin Oncol 2015 ; 45 : 828 – 36 . Google Scholar CrossRef Search ADS PubMed 11 Shinohara S , Kikuchi M , Tona R , et al. . Prognostic impact of p16 and p53 expression in oropharyngeal squamous cell carcinomas . Jpn J Clin Oncol 2014 ; 44 : 232 – 40 . Google Scholar CrossRef Search ADS PubMed 12 Dixon PR , Au M , Hosni A , et al. . Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma . Head Neck 2016 ; 38 : 1347 – 53 . Google Scholar CrossRef Search ADS PubMed 13 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 : 1677 – 84 . Google Scholar CrossRef Search ADS PubMed 14 Loyo M , Johnson JT , Westra WH , et al. . Management of the ‘violated neck’ in the era of chemoradiation . Laryngoscope 2011 ; 121 : 2349 – 58 . Google Scholar CrossRef Search ADS PubMed 15 Allen CT , Lewis JS Jr. , El-Mofty SK , et al. . Human papillomavirus and oropharynx cancer: biology, detection and clinical implications . Laryngoscope 2010 ; 120 : 1756 – 72 . Google Scholar CrossRef Search ADS PubMed 16 Ang KK , Harris J , Wheeler R , et al. . Human papillomavirus and survival of patients with oropharyngeal cancer . N Engl J Med 2010 ; 363 : 24 – 35 . Google Scholar CrossRef Search ADS PubMed 17 Zenga J , Graboyes EM , Haughey BH , et al. . Definitive surgical therapy after open neck biopsy for HPV-related oropharyngeal cancer . Otolaryngol Head Neck Surg 2016 ; 154 : 657 – 66 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Japanese Journal of Clinical OncologyOxford University Press

Published: Apr 21, 2018

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