The Diagnostic Yield of Excisional Biopsy in Cervical Lymphadenopathy: A Retrospective Analysis of 158 Biopsies in Adults

Abstract

Objectives:

Cervical lymph nodes are the most common site of peripheral lymphadenopathy. The underlying etiologies are usually benign and self-limiting but may include malignancies or other severe life-threatening diseases. The aim of the current study was to investigate the various underlying pathologies of cervical lymphadenopathy as assessed by the diagnostic yield of excisional lymph node biopsies of the neck in a tertiary adult practice. The evaluation was performed in light of previous literature and regional epidemiological patterns.

Methods:

Retrospective analysis of hospital charts of 158 adult patients who underwent an excisional biopsy for suspected cervical lymphadenopathy at a tertiary referral head and neck service between January 2017 and December 2019.

Results:

The most common underlying pathology was unspecific and/or reactive lymphadenitis in 44.5% of specimens, followed by malignant disease in 38.6% of cases. An age above 40 years was significantly correlated with an increased likelihood of malignant disease. Lower jugular and posterior triangle lymph nodes showed higher malignancy rates than other groups (100% and 66.7%, respectively). The overall surgical complication rate was 2.5%.

Conclusions:

The results of the current study serve as an indicator of the variety of etiologies causing cervical lymphadenopathy. In particular, given the increasing incidence of malignant diseases in recent decades, the findings should alert physicians to the importance of lymph node biopsy for excluding malignancy in persistent cervical lymphadenopathy especially in older adults. The findings emphasize the value of excisional lymph node biopsy of the neck as a useful diagnostic tool in adult patients with peripheral lymphadenopathy.

Keywords

lymphadenopathy biopsy lymph node excision metastasis surgical pathology

Introduction

Peripheral lymphadenopathy refers to the abnormal size or configuration of peripheral lymph nodes. According to population-based studies in the primary care setting, the incidence of peripheral lymphadenopathy is estimated to be approximately 0.5% of the population.^1,2 Cervical lymph nodes represent the most common localization of peripheral lymphadenopathy.^1,3 While cervical lymphadenopathy is mostly benign in origin,^1
-3 a structured diagnostic workup is recommended to exclude underlying malignancies or other severe life-threatening diseases. If lymphadenopathy does not regress spontaneously within a few weeks, the diagnostic workup usually includes imaging studies, serological examination, and, if necessary, a biopsy. The available biopsy techniques range from minimally invasive fine needle aspiration^4
-6 and core needle biopsy^7,8 to lymph node excision. Fine needle aspiration, although cheap and noninvasive, is not reliable in the diagnosis and classification of malignant lymphomas,^9

-12 which is concerning in the current age of increasing lymphoma incidence.^13

-16 In contrast, excision biopsies have the highest sensitivity and diagnostic yield because they produce sufficient material and simultaneously allow the analysis of the lymph node architecture. These advantages explain why excision biopsies remain the gold standard in the diagnosis of malignant lymphoma. However, excisional lymph node biopsies have the disadvantage of being more invasive and often require general anesthesia in addition to the associated surgical complications.¹⁷

In this study, we report on 158 consecutive excisional lymph node biopsies in adults presenting to a tertiary head and neck surgery clinic. The diagnostic yield is described and distributed according to age and sex. Postoperative complications are listed, and implications for the diagnostic approach of cervical lymphadenopathy are discussed with respect to historical and regional epidemiological patterns.

Patients and Methods

Patient hospital records and imaging data sets of 163 patients who underwent a surgical excisional biopsy for suspected nonresolving cervical lymphadenopathy at the Charité University Hospital Campus Mitte between January 2017 and December 2019 were reviewed. The study was approved by the ethical committee of Charité Medical University (approval number EA1/094/20). Electronic hospital charts, pathology reports, and imaging data sets of all patients were analyzed. The workup protocol included initial empiric antibiotic treatment for 10 days. If the lymphadenopathy did not resolve after 6 weeks, laboratory investigations were performed, including lactate dehydrogenase, infectious disease serology, and complete blood count with white blood cell differential. Of all 163 patients who underwent a biopsy, 5 biopsies eventually revealed other nonlymphoid masses (schwannoma, neurofibroma, and other benign salivary gland tumors) and were thus excluded from further analysis. In all remaining 158 patients, a neck ultrasound was performed preoperatively. The indication for biopsy was determined if the lymph node was resistant to empiric medical therapy, could not be explained by the laboratory investigations, and showed at least one suspicious sonographic feature (short axis diameter more than 1 cm, intranodal necrosis, round configuration, Solbiati index < 2). Fine needle aspiration was generally not performed preoperatively in our center. Flow cytometric analysis was not performed in this cohort. In 135 patients, cross-sectional imaging modalities were additionally employed preoperatively (computed graphy [CT], magnetic resonance imaging, and/or positron emission tomography–computed tomography [PET/CT]). Statistical analysis was performed using IBM SPSS statistics software (version 26). Correlation tests were performed using the Pearson chi-quadrant test. P values of <.05 were considered significant.

Results

Patient Characteristics

Of the 158 patients who met the inclusion criteria in the study period, 84 patients were female (53.2%) and 74 patients were male (46.8%). The minimum and maximum ages (at the time of biopsy) were 17 and 81 years, respectively, with a mean age of 47.9 years (±16.1 years). The age distribution of patients is described in Table 1.

Table 1.

The Distribution of Patients According to Age Group.

	Frequency	%
Age (years)
0-20	6	3.8
21-30	22	13.9
31-40	26	16.4
41-50	29	18.4
51-60	37	23.4
61-99	38	24.1
Total	158	100

Underlying Pathologies

The average diameter of the harvested lymph nodes was 2.7 cm (±0.9 cm). The frequency of underlying pathologies is described in Table 2. The most common underlying pathology was nonspecific changes or reactive lymphadenitis in 71 patients (44.5%), followed by malignant disease in 61 patients (38.6%). Most patients with malignancies showed metastatic disease (30 patients, or 19.0% of total cases), followed by Hodgkin lymphoma in 16 patients (10.1%) and non-Hodgkin lymphoma in 15 patients (9.5%). Of the 15 patients with non-Hodgkin lymphomas, 12 patients had B-cell lymphomas, while 3 patients had T-cell lymphomas. The frequency of encountered subtypes of non-Hodgkin lymphoma is detailed in Table 3. The metastatic disease group was dominated by metastases of unknown primary (11 patients), followed by regional metastases from head and neck squamous cell carcinoma (HNSCC) in patients with a history of HNSCC and newly suspected isolated nodal recurrence (4 patients). To avoid tumor spillage in the neck, an open surgical biopsy in the neck was only performed if there was no suspicious primary lesion. In metastases of unknown primary, the treatment protocol included PET-CT imaging, bilateral tonsillectomy, and panendoscopy of the upper aerodigestive tract with directed biopsies. The remaining metastatic lesions included breast cancer (4 patients), bronchogenic carcinoma (3 patients), neuroendocrine tumors (2 patients), and 1 patient each for thyroid cancer, salivary gland carcinoma, gastric adenocarcinoma, cutaneous melanoma, renal cell carcinoma, and urothelial carcinoma. Infectious pathologies included tuberculous lymphadenitis in 3 patients (1.9%), toxoplasmosis in 4 patients (2.5%), Epstein-Barr virus in 4 patients (2.5%), and fungal lymphadenitis in 1 patient (0.6%). Other miscellaneous benign pathologies included sinus histiocytosis in 9 patients (5.7%), sarcoidosis in 2 patients (1.3%), and finally Castleman disease, IgG4-associated lymphadenopathy, and Kikuchi disease in 1 patient (0.6%).

Table 2.

The Distribution of Specimens According to the Underlying Pathology.

Pathology	Frequency (n)	%
Tuberculosis	3	1.9
Epstein-Barr virus	4	2.5
Toxoplasmosis	4	2.5
Aspergillosis	1	0.6
Total specific infections	12	7.5
Hodgkin lymphoma	16	10.1
Non-Hodgkin lymphoma	15	9.5
Metastasis	30	19.0
Total malignant	61	38.6
Castleman disease	1	0.6
Sinus histiocytosis	9	5.7
IgG4-associated disease	1	0.6
Sarcoidosis	2	1.3
Kikuchi disease	1	0.6
Unspecific or reactive	71	44.5
All cases	158	100

Table 3.

The Distribution of the Subtypes of Non-Hodgkin Lymphoma Specimens.

Pathology	Frequency (n)	%
Diffuse large B-cell lymphoma	2	13.33
Follicular lymphoma	1	6.67
Composite (diffuse large B-cell and follicular lymphomas)	2	13.33
Small lymphocytic lymphoma	4	26.67
Lymphoblastic lymphoma	2	13.33
Burkitt lymphoma	1	6.67
Total B-cell lymphomas	12	80
Peripheral T-cell lymphoma	2	13.33
Angioimmunoblastic lymphoma	1	6.67
Total T-cell lymphomas	3	20
Total non-Hodgkin lymphomas	15	100

Relationship Between Age and Underlying Pathology

Between the ages of 21 and 40, nonspecific reactive lymphadenitis was the most common underlying pathology (24/48 patients, or 50%). From age 41 and above, malignant disease was the most common pathology (49/104 patients, or 47.1%). The distribution of underlying pathologies according to age is detailed in Table 4. An age above 40 years was significantly correlated with a higher likelihood of malignant disease (Pearson χ² test, P < .01).

Table 4.

The Distribution of Specimens According to the Underlying Pathology and Age Group.

Pathology	Age in years
Pathology	<20	21-30	31-40	41-50	51-60	61-99
Tuberculosis	0	0	1	1	1	0
Epstein-Barr virus	1	1	1	0	0	1
Toxoplasmosis	0	0	4	0	0	0
Aspergillosis	0	1	0	0	0	0
Total specific infections	1	2	6	1	1	1
Hodgkin lymphoma	3	3	3	1	4	2
Non-Hodgkin lymphoma	0	0	2	5	2	6
Metastasis	0	0	1	7	11	11
Total malignancies	3	3	6	13	17	19
Castleman disease	1	0	0	0	0	0
Sinus histiocytosis	0	4	1	2	2	0
IgG4-associated disease	0	0	0	1	0	0
Kikuchi disease	0	0	1	0	0	0
Sarcoidosis	0	1	0	1	0	0
Unspecific or reactive	1	12	12	11	17	18
All cases	6	22	26	29	37	38

Lymph Node Localization and Surgical Complications

The localizations of the excised lymph nodes were classified according to their localizations in one of the 5 major groups in the neck according to the 2002 recommendations of the American Academy of Otolaryngology–Head and Neck Surgery (excluding level VI).¹⁸ Of the 158 specimens, the localizations of 20 were unknown and/or could not be clearly attributed to one of the 5 groups. The remaining 138 specimens were distributed according to their localization and the underlying pathology, specifically with respect to malignancy (Table 5). Specimens were most commonly harvested from the upper cervical group (level II) with a total of 56 specimens and least commonly harvested from the lower jugular group (level IV) with a total of 3 specimens. Twenty samples were large enough to encompass multiple regions. Lower jugular and posterior triangle lymph nodes (levels IV and V) were the most likely to be malignant (malignancy rates of 100% and 66.7%, respectively). Upper jugular and submandibular lymph nodes (levels II and I) were the least likely to be malignant (malignancy rates of 21.4% and 23.8%, respectively). We refrained from performing statistical analyses of the association between lymph node localization and the likelihood of malignancy due to the low number of samples in the benign and malignant groups of each individual group and to the nonrandom selection of lymph nodes for biopsy. This nonrandom distribution was based on the fact that the most accessible and/or most suspicious lymph nodes were typically selected for biopsy, regardless of the localization.

Table 5.

The Distribution of Specimens With Regard to Malignancy Risk According to Anatomical Localization.

	Benign	Malignant	Total (%)
Submandibular/submental (level I)	16 (76.2%)	5 (23.8%)	21 (100%)
Upper jugular (level II)	44 (78.6%)	12 (21.4%)	56 (100%)
Middle jugular (level III)	10 (71.4%)	4 (28.6%)	14 (100%)
Lower jugular (level IV)	0 (0%)	3 (100%)	3 (100%)
Posterior triangle (level V)	8 (33.3%)	16 (66.7%)	24 (100%)
Multiple regions	10 (50%)	10 (50%)	20 (100%)

Surgical complications were encountered in 4 patients (2.5%). Two patients suffered from cervical hematoma, which resolved with conservative treatment. One patient developed transient weakness of the marginal mandibular nerve, and 1 patient developed a submandibular abscess postoperatively, which required surgical drainage.

Discussion

The epidemiology of peripheral lymphadenopathy varies widely across countries and ethnicities. In developing nations, lymph node biopsies show much higher rates of infectious pathologies, specifically tuberculosis, which may reach a frequency of 26% to 45% among all cases.^19

-22 In contrast, European studies tend to show much lower rates of tuberculosis with results closer to our data. One British study found the frequency of tuberculosis in 550 patients with peripheral lymphadenopathy to be 4.5%,²³ compared with a frequency of 1.9% in our study. This discrepancy may reflect the slightly higher prevalence of tuberculosis in the United Kingdom than in Germany.²⁴ In addition, Kikuchi disease is known to be more common in Asian populations.^25,26 In our series, 1 patient showed evidence of Kikuchi disease, adding to the few published case studies reporting its incidence in the German population.^27,28

Even focusing on the German population alone, epidemiological shifts can be found across different time periods. For instance, a 1967 study by Matzker²⁹ analyzed a large series of 1553 cervical lymph node biopsies and found a frequency of malignancy amounting to 20.5%, which is considerably lower than the frequency of malignant disease in the current study (38.6%). The higher malignancy rate in our study could potentially be explained by the higher life expectancy in our current era as well as increased industrialization and exposure to oncogenic risk factors. However, such conclusions should be made with caution because the underlying pathologies in the limited number of cases in our study should not be readily extrapolated to the general population but rather used as a general indicator. Furthermore, the amount of additional information provided by modern diagnostic modalities (imaging, molecular, laboratory investigations) represents an inherent selection bias in the patient population being referred for biopsy nowadays compared with the time of the 1967 Matzker’s study. In addition, many of the underlying pathologies were not yet recognized entities in that era, such as HIV or IgG4-associated disease. Nevertheless, this finding was consistent with the well-established trend of an increasing incidence of cancer within young and older adults in recent decades.¹⁶ In particular, the rising epidemic of non-Hodgkin lymphoma has been described in multiple epidemiological studies.^13
-15

Because excision biopsies remain the gold standard for the reliable diagnosis and classification of lymphomas, we argue that this rising lymphoma epidemic will render excision biopsies an essential tool in the diagnosis of cervical lymphadenopathy in coming years. Considering their low complication rate (2.5% in our study), we argue that excision biopsies represent a useful alternative to less invasive biopsy techniques for appropriately selected patients with nonresolving lymphadenopathy, particularly in those with a reasonable suspicion of malignancy. This is especially true in older adults, due to the higher risk of malignancy. Based on our results, level IV and level V cervical lymph nodes may be viewed with more suspicion than those of the other levels of the neck, encouraging the decision to perform an excisional biopsy to exclude malignant disease.

It should be noted that nonspecific reactive lymphadenitis was underrepresented in our study because the majority of cases show a benign self-limiting course and resolve spontaneously. All patients in our series had persistent nonresolving lymphadenopathy for at least 6 weeks, which could not be otherwise explained by a benign infection according to the history, examination, or serologic investigation. For example, no case of HIV was included in our analysis, as patients with serologic evidence of a new HIV infection were not referred for surgical biopsy. In contrast, malignancy was considerably overrepresented in our results, reaching 38.6% of all cases. This finding contrasted sharply with the much lower frequency of malignancy in patients presenting to their primary care physician,^1
-3 which was reported to be between 1% and 2% of all cases.² Thus, due to the tertiary nature of our practice, the revealed pathologies are not representative of the etiologies of cervical lymphadenopathy in the general adult population because of the inherent selection bias. Along with the retrospective design, this represents the main limitation of our study.

Conclusions

The current study highlights the role of surgical excisional biopsy in the diagnosis of cervical lymphadenopathy. The main value of the present study is that it serves as an indicator of the variety of etiologies causing peripheral lymphadenopathy, including some very rare pathologies included in our results. Additionally, our data add support to the established relationship between increasing age and the risk of malignant disease and are consistent with the increasing incidence of malignancy in the current era. The findings should alert otolaryngologists to the value of lymph node excisional biopsy to rule out malignancy in persistent cervical lymphadenopathy, especially in older adults.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Mohamed Bassiouni

Steffen Dommerich

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