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Squamous papilloma arising from within a branchial cleft cyst
Otolaryngology Case Reports 14 (2020) 100136
Contents lists available at ScienceDirect
Otolaryngology Case Reports journal homepage: www.elsevier.com/locate/xocr
Squamous papilloma arising from within a branchial cleft cyst a,∗
b
Matthew K. Lee , Bonnie Balzer , Gene Liu a b
T
a
Division of Otolaryngology – Head and Neck Surgery, Cedars-Sinai Medical Center, 8635 W. 3rd Street, Suite 590W, Los Angeles, CA, 90048, USA Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 8612, Los Angeles, CA, 90048, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: Human papilloma virus Papilloma Branchial cleft anomaly Branchial cleft cyst
Purpose: To report an unusual occurrence of HPV infection manifesting as a squamous papilloma within a branchial cleft cyst. Study design/Methods: Case report and review of literature. Results: A 64-year-old male presented with a history of recurrent oropharyngeal papillomas concurrent with a cystic neck lesion. Initial FNA biopsy was suspicious for a cystic nodal metastasis of squamous cell carcinoma. Upon excision of the neck mass, histopathologic analysis revealed a squamous papilloma arising from within a branchial cleft cyst. HPV positivity was confirmed with in-situ hybridization. The patient remains disease free after 75 months of follow-up. Conclusions: HPV infections of the upper respiratory tract are potentially transmissible into the neck via a branchial anomaly. Oncologic considerations are discussed.
Introduction Branchial cleft anomalies encompass a spectrum of congenital defects that can present as a lateral neck cyst (an isolated epithelial-lined structure without connection to the skin or pharynx), sinus (connecting either the skin or pharynx to a blind pouch in the neck), or fistula (open communicating tract between the skin and pharynx) [1]. In branchial sinuses and fistulas, direct communication of the branchial anomaly with the pharyngeal mucosa potentiates transmission of infections from the upper respiratory tract into the neck [2]. Even in the absence of direct communication, infection of a branchial cleft cyst can often occur concurrently with an upper respiratory tract infection, likely from lymphatic transmission. Most commonly, this will present as an acute swelling and fluctuance of the neck requiring treatment with antibiotics with or without surgical drainage [3]. Human Papilloma Virus (HPV) infections of the upper respiratory tract have been increasing in incidence in the US, and is now the most common form of sexually transmitted infection. HPV has known tumorigenic potential and by some estimates may be implicated in up to 70% of oropharyngeal squamous cell carcinoma [4]. Infections with low-risk subtypes of HPV result in the development of benign mucosal papillomas, a condition known as recurrent respiratory papillomatosis (RRP). The incidence of RRP is bimodal, presenting either in early childhood due to in utero or perinatal transmission or during adulthood
secondary to sexual activity [5]. The spread of HPV infection from the upper respiratory tract to the epithelium of a branchial anomaly, whether via direct communication or lymphatic transmission, has been previously confirmed by PCR studies in excised branchial cleft cysts [6,7]. However, there have been no prior reports in which low-risk HPV positivity was seen concurrently with histopathologic evidence of a benign squamous papilloma arising from within a branchial cleft anomaly. In the current case study, we describe a patient who presented with a history of recurrent respiratory papillomatosis concurrent with a HPV + squamous papilloma of the neck arising from within a branchial cleft cyst. Case report A 64-year-old male presented to a tertiary care medical center for evaluation of a mucosal lesion of the soft palate concurrent with a rightsided neck mass. His past medical history was significant for benign oropharyngeal papillomas, for which he had previously undergone surgical excisions at another institution. On examination, he was noted to have a recurrent papillomas of the soft palate, as well as a right upper neck mass that was fluctuant on palpation. Further diagnostic work-up was performed with a PET/CT, which demonstrated a 3.5 × 2.0 cm cystic neck mass with a hypermetabolic focus (Image 1). The palatal papilloma also demonstrated increased FDG avidity. A fine needle
∗ Corresponding author. Division of Otolaryngology – Head and Neck Surgery, Cedars-Sinai Medical Group, 8635 West 3rd Street, Suite 590W, Los Angeles, CA, 90048, USA. E-mail address: [email protected] (M.K. Lee).
https://doi.org/10.1016/j.xocr.2019.100136 Received 3 October 2019; Accepted 31 October 2019 Available online 16 November 2019 2468-5488/ © 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Otolaryngology Case Reports 14 (2020) 100136
M.K. Lee, et al.
papilloma. (Image 4). No high-grade dysplasia or carcinoma was identified. The patient was followed for a total of 75 months with no evidence of recurrent disease in the neck. He did develop recurrent papillomatosis of the soft palate, which required repeat excision at 6 months and 18 months with Cidofovir injections. He has remained disease free since.
Discussion In the current report, we describe a patient with a known history of RRP who presented concurrently with a HPV + squamous papilloma arising from within a branchial cleft cyst lacking any direct communication with the upper respiratory tract. Upon initial presentation, the neck mass was suspicious for a possible cystic metastasis based on the initial cytology from fine needle aspiration. HPV infection has been recognized as independent risk factor in the pathogenesis of head and neck squamous cell carcinoma, in particular oropharyngeal carcinoma [4,8]. However, histologic analysis of the cystic right neck mass returned consistent with a branchial cleft cyst rather than a cystic metastatic lymph node. Interestingly, the epithelium of the branchial cleft cyst was noted to harbor a benign HPV + squamous papilloma that was histologically similar to the squamous papilloma of the soft palate. Notably, the remainder of the cyst demonstrated the classic histologic appearance of a branchial cleft anomaly. Numerous theories have been proposed regarding the pathogenesis of branchial cleft anomalies. However, the most widely accepted model is that these anomalies originate from the incomplete obliteration of the branchial apparatus remnants during embryogenesis. With branchial fistulas and sinuses, a direct connection exists between the pharyngeal mucosa and the epithelium of the branchial anomaly which provides a potential direct path of transmission of infection [3]. However, branchial cleft cysts do not contain any direct communication to skin or mucosa. Despite this, branchial anomalies will commonly become acute
Image 1. PET/CT demonstrating a 3.5 × 2.0 cm cystic neck mass with a hypermetabolic focus.
aspiration biopsy of the right neck mass was then performed, demonstrating atypical keratinizing squamous cells in a background of acute inflammation. This initial cytology was suspicious for a cystic nodal metastasis of a well-differentiated squamous cell carcinoma. The patient was then taken for a panendoscopy and excisional biopsies of the palatal lesion and right neck mass. Endoscopy showed no evidence of any other mucosal lesions of the aerodigestive tract, and palate biopsy was consistent with benign squamous papilloma. During excision, the neck mass was identified as an epithelial lined cyst, more consistent with branchial cleft anomaly than a cystic lymph node. There was no identifiable communicating tract into the tonsillar fossa. Histopathologic analysis of the neck mass demonstrated a papillomatous lesion arising from within a branchial cleft cyst. The cystic lesion was noted to have peripheral lymphoid aggregates and centrally located ectatic duct-like structures lined by both respiratory and squamous epithelium, consistent with classic histologic appearance of a benign branchial anomaly. Focally, a papillomatous projection can be seen arising from the squamous epithelium lining the ducts of the branchial cleft cyst (Image 2 and 3). In-situ hybridization confirmed positivity for low-risk HPV, supporting the diagnosis of a squamous
Image 2. Lower power H&E. 2
Otolaryngology Case Reports 14 (2020) 100136
M.K. Lee, et al.
Image 3. High power H&E.
Image 4. In-situ hybridization confirming positivity for low-risk HPV.
theory is based upon histopathologic features of branchial anomalies, as most will demonstrate a squamous-lined cyst surrounded by lymphoid epithelium [10]. In this model, the close association between the anomaly and the surrounding lymphatic drainage structures offers one explanation for how upper respiratory infections could spread to an
infected concurrently with a URI, strongly suggesting the possibility of lymphatic transmission of infection [9]. An alternative theory of pathogenesis hypothesizes that branchial cleft cysts arise from within a lymph node, induced by entrapped remnant branchial epithelium resulting in cystic degeneration. This 3
Otolaryngology Case Reports 14 (2020) 100136
M.K. Lee, et al.
Financial disclosure
encapsulated branchial cleft cyst in the absence of a directly communicating tract. In their recent publication, McLean et al. reported a case of a patient with a hypopharyngeal squamous papilloma concurrent with a branchial cleft cyst demonstrating p16 and HPV positivity [9]. The presence of HPV and p16 positivity within an isolated branchial cleft cyst with no communicating tract implicated lymphatic spread as the mode of transmission. A more recent publication reported a series of 4 cases in which HPV DNA was detected by PCR within excised branchial cleft cysts [7]. Neither of these reports demonstrated histologic evidence of squamous papilloma formation within the excision specimen. The current case study similarly describes a patient who presented in adulthood with a chronic oropharyngeal HPV infection which had spread to a branchial cleft cyst in the absence of a directly communicating tract. Interesting, the branchial cleft epithelium not only demonstrated HPV and p16 positivity as has been described in prior reports [6,9], but also demonstrated the presence of a benign squamous papilloma akin to RRP of the upper airway. In light of the established role of HPV in the carcinogenesis of oropharyngeal squamous cell carcinoma, our report has implications regarding the potential for malignant transformation of branchial cleft anomalies in the setting of chronic HPV infection.
None. Declaration of competing interest None. References [1] Prosser JD, Myer CM. Branchial cleft anomalies and thymic cysts. Otolaryngol Clin N Am 2015 Feb;48(1):1–14. [2] Thottam PJ, Bathula SS, Poulik JM, Madgy DN. Complete second branchial cleft anomaly presenting as a fistula and a tonsillar cyst: an interesting congenital anomaly. Ear Nose Throat J 2014 Oct-Nov;93(10–11):466–8. [3] Spinelli C, Rossi L, Strambi S, Piscioneri J, Natale G, Bertocchini A, Messineo A. Branchial cleft and pouch anomalies in childhood: a report of 50 surgical cases. J Endocrinol Investig 2016 May;39(5):529–35. https://doi.org/10.1007/s40618-0150390-8. [4] Tam S, Fu S, Xu L, Krause KJ, Lairson DR, Miao H, Sturgis EM, Dahlstrom KR. The epidemiology of oral human papillomavirus infection in healthy populations: a systematic review and meta-analysis. Oral Oncol 2018 Jul;82:91–9. [5] Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomatosis. Otolaryngol Clin N Am 2012 Jun;45(3):671–94. [viii-ix]. [6] Pai RK, Erickson J, Pourmand N, Kong CS. p16(INK4A) immunohistochemical staining may be helpful in distinguishing branchial cleft cysts from cystic squamous cell carcinomas originating in the oropharynx. Cancer 2009 Apr 25;117(2):108–19. [7] Ikegami T, Uehara T, Deng Z, Kondo S, Maeda H, Kiyuna A, Agena S, Hirakawa H, Yamashita Y, Ganaha A, Suzuki M. Detection of human papillomavirus in branchial cleft cysts. Oncol Lett 2018 Aug;16(2):1571–8. [8] Gooi Z, Chan JY, Fakhry C. The epidemiology of the human papillomavirus related to oropharyngeal head and neck cancer. The Laryngoscope 2016 Apr;126(4):894–900. [9] McLean T, Iseli C, Amott D, Taylor M. Case report of a p16INK4A-positive branchial cleft cyst. J Laryngol Otol 2015 Jun;129(6):611–3. [10] Golledge J, Ellis H. The aetiology of lateral cervical (branchial) cysts: past and present theories. J Laryngol Otol 1994;108:653–9.
Conclusion We report a case of a patient with recurrent respiratory papilomatosis secondary to chronic oropharyngeal HPV infection, who presented with a cystic neck mass demonstrating a benign squamous papilloma arising from within a branchial cleft cyst. To our knowledge, this is the first report in the literature of this clinical phenomenon.
4
Contents lists available at ScienceDirect
Otolaryngology Case Reports journal homepage: www.elsevier.com/locate/xocr
Squamous papilloma arising from within a branchial cleft cyst a,∗
b
Matthew K. Lee , Bonnie Balzer , Gene Liu a b
T
a
Division of Otolaryngology – Head and Neck Surgery, Cedars-Sinai Medical Center, 8635 W. 3rd Street, Suite 590W, Los Angeles, CA, 90048, USA Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 8612, Los Angeles, CA, 90048, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: Human papilloma virus Papilloma Branchial cleft anomaly Branchial cleft cyst
Purpose: To report an unusual occurrence of HPV infection manifesting as a squamous papilloma within a branchial cleft cyst. Study design/Methods: Case report and review of literature. Results: A 64-year-old male presented with a history of recurrent oropharyngeal papillomas concurrent with a cystic neck lesion. Initial FNA biopsy was suspicious for a cystic nodal metastasis of squamous cell carcinoma. Upon excision of the neck mass, histopathologic analysis revealed a squamous papilloma arising from within a branchial cleft cyst. HPV positivity was confirmed with in-situ hybridization. The patient remains disease free after 75 months of follow-up. Conclusions: HPV infections of the upper respiratory tract are potentially transmissible into the neck via a branchial anomaly. Oncologic considerations are discussed.
Introduction Branchial cleft anomalies encompass a spectrum of congenital defects that can present as a lateral neck cyst (an isolated epithelial-lined structure without connection to the skin or pharynx), sinus (connecting either the skin or pharynx to a blind pouch in the neck), or fistula (open communicating tract between the skin and pharynx) [1]. In branchial sinuses and fistulas, direct communication of the branchial anomaly with the pharyngeal mucosa potentiates transmission of infections from the upper respiratory tract into the neck [2]. Even in the absence of direct communication, infection of a branchial cleft cyst can often occur concurrently with an upper respiratory tract infection, likely from lymphatic transmission. Most commonly, this will present as an acute swelling and fluctuance of the neck requiring treatment with antibiotics with or without surgical drainage [3]. Human Papilloma Virus (HPV) infections of the upper respiratory tract have been increasing in incidence in the US, and is now the most common form of sexually transmitted infection. HPV has known tumorigenic potential and by some estimates may be implicated in up to 70% of oropharyngeal squamous cell carcinoma [4]. Infections with low-risk subtypes of HPV result in the development of benign mucosal papillomas, a condition known as recurrent respiratory papillomatosis (RRP). The incidence of RRP is bimodal, presenting either in early childhood due to in utero or perinatal transmission or during adulthood
secondary to sexual activity [5]. The spread of HPV infection from the upper respiratory tract to the epithelium of a branchial anomaly, whether via direct communication or lymphatic transmission, has been previously confirmed by PCR studies in excised branchial cleft cysts [6,7]. However, there have been no prior reports in which low-risk HPV positivity was seen concurrently with histopathologic evidence of a benign squamous papilloma arising from within a branchial cleft anomaly. In the current case study, we describe a patient who presented with a history of recurrent respiratory papillomatosis concurrent with a HPV + squamous papilloma of the neck arising from within a branchial cleft cyst. Case report A 64-year-old male presented to a tertiary care medical center for evaluation of a mucosal lesion of the soft palate concurrent with a rightsided neck mass. His past medical history was significant for benign oropharyngeal papillomas, for which he had previously undergone surgical excisions at another institution. On examination, he was noted to have a recurrent papillomas of the soft palate, as well as a right upper neck mass that was fluctuant on palpation. Further diagnostic work-up was performed with a PET/CT, which demonstrated a 3.5 × 2.0 cm cystic neck mass with a hypermetabolic focus (Image 1). The palatal papilloma also demonstrated increased FDG avidity. A fine needle
∗ Corresponding author. Division of Otolaryngology – Head and Neck Surgery, Cedars-Sinai Medical Group, 8635 West 3rd Street, Suite 590W, Los Angeles, CA, 90048, USA. E-mail address: [email protected] (M.K. Lee).
https://doi.org/10.1016/j.xocr.2019.100136 Received 3 October 2019; Accepted 31 October 2019 Available online 16 November 2019 2468-5488/ © 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Otolaryngology Case Reports 14 (2020) 100136
M.K. Lee, et al.
papilloma. (Image 4). No high-grade dysplasia or carcinoma was identified. The patient was followed for a total of 75 months with no evidence of recurrent disease in the neck. He did develop recurrent papillomatosis of the soft palate, which required repeat excision at 6 months and 18 months with Cidofovir injections. He has remained disease free since.
Discussion In the current report, we describe a patient with a known history of RRP who presented concurrently with a HPV + squamous papilloma arising from within a branchial cleft cyst lacking any direct communication with the upper respiratory tract. Upon initial presentation, the neck mass was suspicious for a possible cystic metastasis based on the initial cytology from fine needle aspiration. HPV infection has been recognized as independent risk factor in the pathogenesis of head and neck squamous cell carcinoma, in particular oropharyngeal carcinoma [4,8]. However, histologic analysis of the cystic right neck mass returned consistent with a branchial cleft cyst rather than a cystic metastatic lymph node. Interestingly, the epithelium of the branchial cleft cyst was noted to harbor a benign HPV + squamous papilloma that was histologically similar to the squamous papilloma of the soft palate. Notably, the remainder of the cyst demonstrated the classic histologic appearance of a branchial cleft anomaly. Numerous theories have been proposed regarding the pathogenesis of branchial cleft anomalies. However, the most widely accepted model is that these anomalies originate from the incomplete obliteration of the branchial apparatus remnants during embryogenesis. With branchial fistulas and sinuses, a direct connection exists between the pharyngeal mucosa and the epithelium of the branchial anomaly which provides a potential direct path of transmission of infection [3]. However, branchial cleft cysts do not contain any direct communication to skin or mucosa. Despite this, branchial anomalies will commonly become acute
Image 1. PET/CT demonstrating a 3.5 × 2.0 cm cystic neck mass with a hypermetabolic focus.
aspiration biopsy of the right neck mass was then performed, demonstrating atypical keratinizing squamous cells in a background of acute inflammation. This initial cytology was suspicious for a cystic nodal metastasis of a well-differentiated squamous cell carcinoma. The patient was then taken for a panendoscopy and excisional biopsies of the palatal lesion and right neck mass. Endoscopy showed no evidence of any other mucosal lesions of the aerodigestive tract, and palate biopsy was consistent with benign squamous papilloma. During excision, the neck mass was identified as an epithelial lined cyst, more consistent with branchial cleft anomaly than a cystic lymph node. There was no identifiable communicating tract into the tonsillar fossa. Histopathologic analysis of the neck mass demonstrated a papillomatous lesion arising from within a branchial cleft cyst. The cystic lesion was noted to have peripheral lymphoid aggregates and centrally located ectatic duct-like structures lined by both respiratory and squamous epithelium, consistent with classic histologic appearance of a benign branchial anomaly. Focally, a papillomatous projection can be seen arising from the squamous epithelium lining the ducts of the branchial cleft cyst (Image 2 and 3). In-situ hybridization confirmed positivity for low-risk HPV, supporting the diagnosis of a squamous
Image 2. Lower power H&E. 2
Otolaryngology Case Reports 14 (2020) 100136
M.K. Lee, et al.
Image 3. High power H&E.
Image 4. In-situ hybridization confirming positivity for low-risk HPV.
theory is based upon histopathologic features of branchial anomalies, as most will demonstrate a squamous-lined cyst surrounded by lymphoid epithelium [10]. In this model, the close association between the anomaly and the surrounding lymphatic drainage structures offers one explanation for how upper respiratory infections could spread to an
infected concurrently with a URI, strongly suggesting the possibility of lymphatic transmission of infection [9]. An alternative theory of pathogenesis hypothesizes that branchial cleft cysts arise from within a lymph node, induced by entrapped remnant branchial epithelium resulting in cystic degeneration. This 3
Otolaryngology Case Reports 14 (2020) 100136
M.K. Lee, et al.
Financial disclosure
encapsulated branchial cleft cyst in the absence of a directly communicating tract. In their recent publication, McLean et al. reported a case of a patient with a hypopharyngeal squamous papilloma concurrent with a branchial cleft cyst demonstrating p16 and HPV positivity [9]. The presence of HPV and p16 positivity within an isolated branchial cleft cyst with no communicating tract implicated lymphatic spread as the mode of transmission. A more recent publication reported a series of 4 cases in which HPV DNA was detected by PCR within excised branchial cleft cysts [7]. Neither of these reports demonstrated histologic evidence of squamous papilloma formation within the excision specimen. The current case study similarly describes a patient who presented in adulthood with a chronic oropharyngeal HPV infection which had spread to a branchial cleft cyst in the absence of a directly communicating tract. Interesting, the branchial cleft epithelium not only demonstrated HPV and p16 positivity as has been described in prior reports [6,9], but also demonstrated the presence of a benign squamous papilloma akin to RRP of the upper airway. In light of the established role of HPV in the carcinogenesis of oropharyngeal squamous cell carcinoma, our report has implications regarding the potential for malignant transformation of branchial cleft anomalies in the setting of chronic HPV infection.
None. Declaration of competing interest None. References [1] Prosser JD, Myer CM. Branchial cleft anomalies and thymic cysts. Otolaryngol Clin N Am 2015 Feb;48(1):1–14. [2] Thottam PJ, Bathula SS, Poulik JM, Madgy DN. Complete second branchial cleft anomaly presenting as a fistula and a tonsillar cyst: an interesting congenital anomaly. Ear Nose Throat J 2014 Oct-Nov;93(10–11):466–8. [3] Spinelli C, Rossi L, Strambi S, Piscioneri J, Natale G, Bertocchini A, Messineo A. Branchial cleft and pouch anomalies in childhood: a report of 50 surgical cases. J Endocrinol Investig 2016 May;39(5):529–35. https://doi.org/10.1007/s40618-0150390-8. [4] Tam S, Fu S, Xu L, Krause KJ, Lairson DR, Miao H, Sturgis EM, Dahlstrom KR. The epidemiology of oral human papillomavirus infection in healthy populations: a systematic review and meta-analysis. Oral Oncol 2018 Jul;82:91–9. [5] Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomatosis. Otolaryngol Clin N Am 2012 Jun;45(3):671–94. [viii-ix]. [6] Pai RK, Erickson J, Pourmand N, Kong CS. p16(INK4A) immunohistochemical staining may be helpful in distinguishing branchial cleft cysts from cystic squamous cell carcinomas originating in the oropharynx. Cancer 2009 Apr 25;117(2):108–19. [7] Ikegami T, Uehara T, Deng Z, Kondo S, Maeda H, Kiyuna A, Agena S, Hirakawa H, Yamashita Y, Ganaha A, Suzuki M. Detection of human papillomavirus in branchial cleft cysts. Oncol Lett 2018 Aug;16(2):1571–8. [8] Gooi Z, Chan JY, Fakhry C. The epidemiology of the human papillomavirus related to oropharyngeal head and neck cancer. The Laryngoscope 2016 Apr;126(4):894–900. [9] McLean T, Iseli C, Amott D, Taylor M. Case report of a p16INK4A-positive branchial cleft cyst. J Laryngol Otol 2015 Jun;129(6):611–3. [10] Golledge J, Ellis H. The aetiology of lateral cervical (branchial) cysts: past and present theories. J Laryngol Otol 1994;108:653–9.
Conclusion We report a case of a patient with recurrent respiratory papilomatosis secondary to chronic oropharyngeal HPV infection, who presented with a cystic neck mass demonstrating a benign squamous papilloma arising from within a branchial cleft cyst. To our knowledge, this is the first report in the literature of this clinical phenomenon.
4