Editor’s Comments

This article is noteworthy for its exploration of a rare case involving a midline branchial cleft cyst in a 77-year-old male, presenting as a left anterior cervical cystic mass. Initially, it was suspected to be an infrahyoid thyroglossal duct cyst based on imaging, but the diagnosis was revised after surgical excision through histopathological analysis. This case, along with the mention of only three other similar cases in the literature, significantly enriches the understanding of branchial cleft cysts, particularly their atypical presentations and the importance of considering them in the differential diagnosis of midline neck masses in adults. The article's scholarly merit and unique case study make it a worthy candidate for publication. However, this article may require revisions due to identifiable issues such as a constrained comparative analysis and an inadequate review of existing literature, as indicated below.

1. This manuscript is remarkable for its investigation into a particularly uncommon condition, as evidenced by only three comparable cases found in the existing literature. The author's analysis of these four cases is commendable, providing valuable insights into the diagnosis and treatment of this rare disease. By choosing such an infrequent topic, the author enhances the article's uniqueness. In my opinion, the systematic compilation of rare case data is essential and of significant importance for the integrated analysis of big data in future research endeavors. It is advised that the author seizes this opportunity to perform a comprehensive comparative analysis of the cases presented. Doing so would elevate the manuscript from a mere case report to an in-depth literature review. This broader approach would not only enrich our collective understanding but also offer essential information to the medical community for the effective handling of this rare disease. I recognize that the Korean case is originally recorded in the Korean language; nonetheless, employing software tools like Google Translate allows for a thorough portrayal of the intricate specifics. To illustrate this, I have included the translated version of the article for your reference. The table and its explanatory text, which should be referenced in the Discussion section, are presented here to exemplify the concept: The table presents a comparative analysis of four branchial cleft cyst cases, highlighting variations in demographics, symptoms, and mass characteristics across different global regions. These cases, from India, Korea, and the USA, span a wide age range (3 to 77 years), demonstrating the condition's occurrence at various life stages. Differences are observed in mass location, size, and imaging findings. Notably, fine needle aspiration was not consistently used, and while all cases underwent excisional biopsy, intraoperative findings varied. The absence of complications in all cases indicates effective management, providing valuable insights into the condition's diagnosis and treatment.
   ResponseThank you for this recommendation. A comparative analysis of the rare case data provides deeper understanding into the varying presentations, diagnostic considerations, and management strategies of branchial cleft cysts. We have also obtained more thorough histopathological findings for our specific clinical case, which has been added to the comparative table. We have included the comparative table with revisions and implemented further discussion, beginning line 68 as follows:
   
   A comparative analysis of the four branchial cleft cyst cases, including the current case, highlights variations in demographics, symptoms, and mass characteristics across different global regions including India, Korea, and the United States (Table 1). These cases reflect a wide age range from 3 to 77 years of age. There are observed differences regarding mass location, size, and imaging findings. Aggarwal et al. reported a branchial cleft cyst in the midline of the neck inferior to the hyoid bone [7]. Narayana et al. described a midline branchial cleft cyst in the submental region [8]. Baek et al. provided evidence of a midline mass superficial to the sternohyoid [9]. Notably, fine needle aspiration (FNA) was only used in one of the four cases, which provided evidence of a small number of lymphocytes [9]. While all cases underwent excisional biopsy, intraoperative findings varied, often showing adherence to nearby structures. Intraoperative findings from Aggarwal et al. exhibited adherence to strap musculature and pre-tracheal fascia [7]. Baek et al. detailed the adhesion of the mass to the right sternohyoid muscle [9]. Our intraoperative findings observed mass adherence to the thyroid cartilage with a lateral tract beyond the left lesser cornu of the hyoid bone. In three cases, histopathologic findings described the cystic wall lining with stratified squamous and ciliated columnar epithelium, characteristic of branchial cleft cysts [8, 9]. Following excisional biopsy in all four cases, the absence of complications in all cases indicates effective management, providing valuable insights into the condition’s atypical presentation, diagnosis, and treatment. As highlighted in the comparative analysis of the four reported cases, midline branchial cleft cysts represent an extremely rare presentation that warrants consideration in the differential diagnoses of neck masses.
    
2. When faced with a similar case as described in the report, particularly one involving a branchial cleft cyst that was initially misdiagnosed as an infrahyoid thyroglossal duct cyst due to its unusual midline presentation, it is prudent to consider alternative strategies for its management. For instance, the implementation of fine needle aspiration biopsy prior to surgical intervention could be a prudent approach. This less invasive procedure has the potential to yield cytological data that might either corroborate or challenge the preliminary diagnosis. Such information could significantly enhance the preoperative assessment, leading to a more precise understanding of the lesion's pathology. Engaging in this discourse is instrumental in deepening the comprehension of the management strategies for uncommon presentations of midline neck branchial cleft cysts, thereby contributing to more informed and effective clinical decision-making processes.
   ResponseDiscussion of preoperative FNA biopsy is an important consideration regarding the potential benefits and drawbacks in the management of cystic neck lesions, particularly in our case of a midline branchial cleft cyst initially misdiagnosed as an infrahyoid thyroglossal duct cyst. We have included a more thorough discussion of the diagnostic considerations for preoperative FNA biopsy, beginning line 122 as follows:
   
   Diagnostic considerations of midline neck masses involve the implementation of FNA biopsy prior to surgical intervention. It is noteworthy that of the four cases reported, only one case utilized FNA prior to tumor excision. In our patient case, the initial presentation strongly suggested thyroglossal duct cyst due to its clinical presentation as a midline neck mass with anatomic relation to the hyoid bone on radiographic imaging. Therefore, FNA was not performed, with intentions of excisional biopsy for definitive diagnosis. However, the misclassification of cystic metastases as branchial cleft cysts may result in delayed diagnoses and treatments of urgent cases, with premature open biopsy of metastatic cancer, decreased survival rates, intensified local wound necrosis, and heightened risks of cancer recurrence [10]. As a result, some argue in favor of FNA biopsy as a less invasive approach, producing cytological data to guide differential diagnoses and preoperative assessments. To enhance the use of FNA cytology in distinguishing between branchial cleft cysts and HNSCC, Layfield et al. analyzed 19 cytologic features in 33 histologically confirmed cystic lesions, 21 HNSCC and 12 branchial cleft cysts [17]. Through multivariant analysis, the most helpful cytologic features included high nuclear cytoplasmic ratio, irregular nuclear membranes, and small cell clusters [17]. FNA is highly reasonable for presenting neck lesions with a heightened suspicion of malignancy, particularly in cystic lateral neck masses and solid tumors of the neck. Sira et al. identified 47 cases of metastatic cancers presenting as solitary neck masses of unknown primary origin [14]. Remarkably, 6.4% of these cases were initially misdiagnosed as branchial cleft cysts, later confirmed as HNSCC. Therefore, for adults with lateral cervical cystic masses, the recommended protocol includes radiological CT or MRI imaging and FNA cytology, followed by an excisional biopsy with intraoperative frozen section evaluation [14].
   
   Nevertheless, the necessity of implementing FNA biopsy in search of a primary tumor prior to midline neck cyst excision remains debatable. Detecting cancer within a midline neck cyst presents a significant challenge, as radiological methods are often insufficient, and FNA biopsy's reliability is questionable [10, 18]. Some studies report FNA sensitivities ranging from 30-50% with up to 50-67% of false negatives in cystic neck metastases [11,12]. The difficulty in implementing FNA biopsy as a reliable tool for diagnosing cystic metastases may be a result of the often low cell density of the aspirate and the high presence of inflammatory cells, dystrophic epithelial cells, and cellular debris [11,12]. As a result, excisional biopsy is essential for definitive diagnosis. All four reported cases of midline branchial cleft cysts underwent excisional biopsy with confirmatory diagnosis via histopathological analysis. In assessing the use of FNA biopsy prior to tumor excision, critics further raise concerns about the cost-effectiveness and risk of subjecting patients to unnecessary procedures, considering that many cystic lesions are typically simple, benign branchial cleft cysts.
    
3. Although the caption confirms the diagnosis of a branchial cleft cyst, it does not detail the specific histopathological features observed in each image that lead to this diagnosis, such as the type of epithelial lining or the characteristics of the surrounding stroma. The caption assumes that readers are already acquainted with the microscopic characteristics of a branchial cleft cyst, which is an assumption that may not apply to all readers. A more thorough description of the histological features present would be beneficial for educational purposes. For instance, the descriptions for the respective panels might read as follows: (A) Low magnification view (Hematoxylin and Eosin stain, x 40) reveals the cystic space. The surrounding tissue exhibits inflammatory infiltration, with red erythrocytes within the cystic space indicating possible hemorrhage. (B) At medium magnification (H&E, x 100), the cyst lining is more discernible, characterized by stratified epithelium and a dense lymphoid infiltrate in the stroma, typical of branchial cleft cysts. Such lymphoid tissue presence supports the diagnosis. (C) High magnification (H&E, x 200) allows for closer examination of the cyst lining, which may consist of stratified squamous, pseudostratified, or ciliated columnar epithelium, consistent with the diagnosis of a branchial cleft cyst. It is advisable for the authors to seek confirmation from a pathologist to ensure the accuracy of the caption.
   ResponseTo enhance the educational utilization of the histopathological findings in Figure 2, we have obtained input from the Department of Pathology at Bay Pines Veterans Affairs Healthcare System in Bay Pines, FL, USA who verified the following description: (A) Low magnification view (H&E, x 40) reveals the cystic space. (B) Medium magnification (H&E, x 100) and (C) high magnification (H&E, x 200) views reveal focally excoriated cyst lining of stratified, ciliated columnar epithelium. The cyst wall shows focally nodular lymphocytic infiltrate. The overall histological features are consistent with a branchial cleft cyst. The specific histopathological findings are reflective in Figure 2 and the postoperative details of the case presentation in line 50 as follows: Histopathological examination of the left infrahyoid mass revealed a focally excoriated cyst lining of stratified, ciliated columnar epithelium with focally nodular lymphocytic infiltrate, confirming the diagnosis of a branchial cleft cyst (Figure 2).

Reviewer 1 Comments

The article presents a unique case of a branchial cleft cyst, initially misidentified as an infrahyoid thyroglossal duct cyst, attributed to its rare midline location. This case underscores the vital importance for healthcare professionals to include branchial cleft cysts in the differential diagnosis of midline neck masses. While the report is informative and adds significant value to the medical literature, it requires further enhancement in terms of detailed information, contextual depth, and improved presentation to meet the high standards of a reputable medical journal. To be considered suitable for publication, the article needs to address these specific issues and enrich its content to ensure a rigorous presentation.

1. The authors should clarify whether the patient underwent preoperative fine needle aspiration (FNA). In this article, it is noteworthy that of the four cases reported, only one was reported to undergo FNA prior to tumor excision. This emphasizes the necessity of conducting a detailed investigation into the role of preoperative FNA, specifically aiming to assess thoroughly its benefits and drawbacks. Supporters emphasize that erroneously diagnosing a cystic metastasis as a branchial cleft cyst can result in significant problems, including the mishandling of urgent cases as non-urgent, which further exacerbates delays in diagnosis. This misclassification can also lead to premature open biopsies of metastatic cancer, negatively affecting survival rates, intensifying local wound necrosis, and heightening the risks of recurrence [PMID: 7861083]. In their five-year study, Sira et al. identified 47 cases of metastatic cancers presenting as solitary neck masses of unknown primary origin. Remarkably, 6.4% of these cases (3 lesions) were initially misdiagnosed as branchial cleft cysts, later confirmed as squamous cell carcinomas. Therefore, for adults with “lateral” cervical cystic masses, the recommended protocol includes radiological imaging (CT or MRI) and FNA cytology, followed by an excisional biopsy of the cystic mass with intraoperative frozen section evaluation [PMID: 21774450]. Nevertheless, the necessity of searching for a primary tumor prior to “midline” neck cyst excision remains debatable. The challenge lies in detecting cancer within a cyst, as radiological methods often fall short [PMID: 2013199], and FNA biopsy's reliability is questionable [PMID: 7861083]. As a result, excision biopsy is essential for definitive diagnosis. Critics further raise concerns about cost-effectiveness and the risk of subjecting patients to unnecessary procedures, considering that many cystic lesions are typically simple branchial cleft cysts. To provide a balanced perspective in this paper, it is suggested that the authors include these contrasting viewpoints in the Discussion section, offering a comprehensive view of the management of these cystic lesions.
   ResponseFine needle aspiration (FNA) is reasonable for clinical presentations of neck masses with heightened cancer risk or suspicion of malignancy, particularly in lateral neck masses. In our patient case, the initial presentation strongly suggested thyroglossal duct cyst due to its clinical presentation as a midline neck mass with anatomic relation to the hyoid bone on radiographic imaging. Therefore, FNA was not performed, with intentions of excisional biopsy for definitive diagnosis. However, comparative analysis of the few reported cases of atypical branchial cleft cysts warrants further discussion of the necessity for preoperative FNA in guiding future management of rare presentations of branchial cleft cysts. We have included a balanced discussion of the benefits and drawbacks of preoperative FNA biopsy to contribute to a larger discussion of managing atypical cystic lesions of the neck, beginning line 122 as follows:
   
   Diagnostic considerations of midline neck masses involve the implementation of FNA biopsy prior to surgical intervention. It is noteworthy that of the four cases reported, only one case utilized FNA prior to tumor excision. In our patient case, the initial presentation strongly suggested thyroglossal duct cyst due to its clinical presentation as a midline neck mass with anatomic relation to the hyoid bone on radiographic imaging. Therefore, FNA was not performed, with intentions of excisional biopsy for definitive diagnosis. However, the misclassification of cystic metastases as branchial cleft cysts may result in delayed diagnoses and treatments of urgent cases, with premature open biopsy of metastatic cancer, decreased survival rates, intensified local wound necrosis, and heightened risks of cancer recurrence [10]. As a result, some argue in favor of FNA biopsy as a less invasive approach, producing cytological data to guide differential diagnoses and preoperative assessments. To enhance the use of FNA cytology in distinguishing between branchial cleft cysts and HNSCC, Layfield et al. analyzed 19 cytologic features in 33 histologically confirmed cystic lesions, 21 HNSCC and 12 branchial cleft cysts [17]. Through multivariant analysis, the most helpful cytologic features included high nuclear cytoplasmic ratio, irregular nuclear membranes, and small cell clusters [17]. FNA is highly reasonable for presenting neck lesions with a heightened suspicion of malignancy, particularly in cystic lateral neck masses and solid tumors of the neck. Sira et al. identified 47 cases of metastatic cancers presenting as solitary neck masses of unknown primary origin [14]. Remarkably, 6.4% of these cases were initially misdiagnosed as branchial cleft cysts, later confirmed as HNSCC. Therefore, for adults with lateral cervical cystic masses, the recommended protocol includes radiological CT or MRI imaging and FNA cytology, followed by an excisional biopsy with intraoperative frozen section evaluation [14].
   
   Nevertheless, the necessity of implementing FNA biopsy in search of a primary tumor prior to midline neck cyst excision remains debatable. Detecting cancer within a midline neck cyst presents a significant challenge, as radiological methods are often insufficient, and FNA biopsy's reliability is questionable [10, 18]. Some studies report FNA sensitivities ranging from 30-50% with up to 50-67% of false negatives in cystic neck metastases [11,12]. The difficulty in implementing FNA biopsy as a reliable tool for diagnosing cystic metastases may be a result of the often low cell density of the aspirate and the high presence of inflammatory cells, dystrophic epithelial cells, and cellular debris [11,12]. As a result, excisional biopsy is essential for definitive diagnosis. All four reported cases of midline branchial cleft cysts underwent excisional biopsy with confirmatory diagnosis via histopathological analysis. In assessing the use of FNA biopsy prior to tumor excision, critics further raise concerns about the cost-effectiveness and risk of subjecting patients to unnecessary procedures, considering that many cystic lesions are typically simple, benign branchial cleft cysts.
    
2. Squamous cell carcinoma in the head and neck (HNSCC) often results in metastasis to deep cervical lymph nodes, typically presenting as firm masses. These masses, especially cervical metastases arising from HPV-positive HNSCC, can sometimes be mistakenly diagnosed as branchial cleft cysts at levels II, III, and IV [PMID 7861083; PMID 15792616; PMID 18383529; PMID 28891406]. The challenge in clinical practice lies in differentiating malignant cystic neck lesions from benign cysts, such as branchial cleft cysts, due to their similar radiographic profiles and the frequently insufficient diagnostic yield of fine needle aspiration. Age plays a significant role in the differential diagnosis, with a heightened probability of metastatic cervical lymph nodes in patients over 40 [PMID 7861083]. Literature reports suggest that the incidence of carcinoma in cervical cysts initially thought to be branchial cleft cysts ranges from 4% to 24%, and this figure escalates to as much as 80% in individuals over 40 years of age [PMID 21774450]. Therefore, in the case of older patients presenting with neck masses, a thorough preoperative evaluation becomes imperative given the increased risk of malignancy associated with age. This issue merits further exploration and discussion. It is recommended that the authors incorporate these perspectives into the Discussion section.
   ResponseThe four reported cases of atypical branchial cleft cysts most certainly warrant further exploration of the diagnostic challenges in distinguishing benign cystic masses from malignant cystic lesions, particularly squamous cell carcinoma in the head and neck. Our patient’s advanced age at 77 years old, enhancing risk factors such as tobacco use, and presence of a nontender, enlarging neck mass resulting in persistent symptoms of throat clearing and dysphagia justified a thorough clinical evaluation due to the higher risk of malignancy. However, the patient’s consistent initial presentation with thyroglossal duct cyst, given the midline location, physical examination findings, and imaging, decreased our suspicion for cancerous etiologies. Our case emphasizes the importance to consider branchial cleft cysts in the differential diagnoses of midline neck masses and the necessity to evaluate the effectiveness of varying diagnostic strategies of cystic neck lesions, particularly in patient populations at an increased risk for malignancy. A thorough discussion of heightened risk factors for malignancy and diagnostic considerations for branchial cleft cysts has been implemented, beginning at line 99 as follows:
   
   Another important diagnosis to consider includes squamous cell carcinoma of the head and neck (HNSCC), which typically presents as firm masses and often results in metastasis to nearby deep cervical lymph nodes. These masses, particularly those with cervical metastases from HPV-positive HNSCC, may be mistakenly diagnosed as branchial cleft cysts at the levels of II, III, and IV due to their typical location in the lateral neck [10-13]. As a result, mistaken diagnoses of branchial cleft cysts may lead to significant detriments in patient care such as delayed treatments of urgent cases and reduction in survival rates. Several challenges in distinguishing malignant cystic neck lesions and benign branchial cleft cysts derive from the similar radiographic profiles and the often insufficient diagnostic yield of FNA biopsy [10,11]. One significant consideration for the differential diagnoses of neck masses is age, with a heightened probability of metastatic cervical lymph nodes in patients over 40 [10]. As reported in the current literature, the incidence of carcinoma in cervical cysts initially considered as branchial cleft cysts ranges from 4% to 24%, escalating to 80% in individuals over 40 years of age [14-16]. Therefore, in patients over 40 years of age presenting with neck masses, a thorough preoperative evaluation becomes imperative given the increased risk of malignancy. Our patient’s advanced age at 77 years old, enhancing risk factors such as alcohol and tobacco use, and presence of a nontender, enlarging neck mass with persistent throat clearing and dysphagia justified a comprehensive clinical evaluation due to the higher risk of malignancy. However, the patient’s consistent initial presentation with thyroglossal duct cyst, given the midline location, physical examination findings, and imaging, decreased our suspicion for cancerous etiologies. Our case emphasizes the importance to consider branchial cleft cysts in the differential diagnoses of midline neck masses and the necessity to evaluate the effectiveness of varying diagnostic strategies of cystic neck lesions, particularly in patient populations at an increased risk for malignancy.

Reviewer 2 Comments

The article highlights an extraordinary medical case—a branchial cleft cyst located in an unexpected midline position. Typically found along the anterior border of the sternocleidomastoid muscle in the lateral neck, this rare occurrence challenges conventional diagnostic expectations. Initially misidentified as an infrahyoid thyroglossal duct cyst based on imaging, the definitive diagnosis emerged only through postoperative histopathological analysis. This case significantly contributes to our understanding of branchial cleft cysts and their unusual presentations in adults, given that there are only three similar cases documented in the literature. In summary, this article is a must-read for medical professionals as it not only enriches their understanding of branchial cleft cysts, particularly in their atypical presentations, but also reinforces the principles of thorough evaluation and differential diagnosis in clinical practice through its review of literature. Considering the article's distinctiveness and substantial academic merit, I contend that it merits publication in its current form, subject to the implementation of some minor revisions.

1. The patient's medical history has not been adequately detailed. For individuals presenting with neck masses, it is crucial to ascertain and document any history of smoking, alcohol use, and engagement in behaviors typically correlated with a heightened cancer risk.
   ResponseTo provide more details regarding the patient’s medical history, we have included pertinent social history such as tobacco use, alcohol use, recreational drug use in the Case Presentation line 36 as follows: Pertinent social history includes intermittent tobacco use, alcohol use of two beers a day, and denial of recreational drug use.
    
2. In the four documented cases referenced, including the current instance, there seems to be an absence of thorough inspection of mucosal areas (such as the larynx, tongue base, and pharynx), utilizing either mirror or endoscopic approaches based on the clinician's discretion. In elderly patients, fiberscope is particularly recommended for an extensive examination of the upper aerodigestive tract, especially when symptoms like persistent throat clearing and dysphagia are present. The current case study lacks details on these critical examinations. The authors are advised to include these details.
   ResponseFlexible nasolaryngoscopy was performed in our patient case with unremarkable findings regarding the patient’s clinical symptoms of persistent throat clearing and dysphagia. We have included the specific findings in the Case Presentation line 29 as follows: Further evaluation with flexible nasolaryngoscopy was unremarkable, showing evidence of nasal patency of the right nasal cavity, no observed lesions or masses on the base of tongue and vallecula, mobile true vocal cords without lesions, and good laryngeal swallow.

Editorial Comments

1. Introduce abbreviations with their full terms at their initial occurrence in the text. For instance, the abbreviation "SCM" should be spelled out as "sternocleidomastoid" when first mentioned.
   ResponseThe full-term sternocleidomastoid with its corresponding abbreviation, SCM, has been included in the Introduction line 17.
    
2. Following our publication's established guidelines, we respectfully urge authors to provide their academic and professional credentials, such as BS or MD. Including these qualifications enables readers to evaluate the authors' expertise and professional backgrounds, ultimately bolstering the overall credibility and integrity of the published content.
   ResponseThe credentials have been added to all authors as reflected on the Title Page of the manuscript.
    
3. Please revise the title to make it more informative. If needed, refer to the example provided below for guidance: Navigating Uncharted Waters: A Comprehensive Literature Review and Rare Case Study of a Midline Branchial Cleft Cyst Initially Misdiagnosed as Thyroglossal Duct Cyst.
   ResponseThank you for the recommendation. The revision has been included in the Title page to reflect a more informative title for readers.

Sia MJ, Kapadia IH, Hahn JS. Midline branchial cleft cyst initially misdiagnosed as a thyroglossal duct cyst: A rare case study and literature review. Arch Otorhinolaryngol Head Neck Surg. 2024;8(1):2. https://doi.org/10.24983/scitemed.aohns.2024.00181