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Human papillomavirus-related multiphenotypic sinonasal carcinoma (HMSC) is a rare primary tumor of the sinonasal tract that has been reported recently. It is reportedly associated with human papillomavirus infection. The tumor presents with glandular cyst-like histology, but some cases exhibit squamous epithelialization and are positive on p16 immunohistochemical staining. The clinical picture and treatment of this disease have not been established. However, this report describes a recurrent case of this disease treated with salvage surgery. The patient was a 61-year-old woman who presented to the previous doctor with a chief complaint of nasal obstruction. A localized tumor was found in the left nasal cavity and was resected under endoscopic guidance. The postoperative pathological diagnosis was HMSC. Twenty-one months after the surgery, local recurrence was observed, and the patient was referred to our hospital. Since the recurrent lesion had widely infiltrated outside the nasal cavity, extensive resection and reconstructive surgery were performed. Postoperative radiotherapy was performed as an additional treatment. Notably, 13 months have passed since the salvage surgery, and no recurrence has been observed to date.
Human papillomavirus (HPV)-related carcinomas of the head and neck commonly occur in the oropharyngeal area. A recent study demonstrated that HPV type 16 was responsible for up to 80% of oropharyngeal carcinomas [
Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience.
]. The sinonasal HPV-related carcinoma with adenoid cyst-like features is discussed in the fourth edition of the World Health Organization (WHO) classification of head and neck tumors. As the name implies, the histology of this tumor resembles quite closely that of adenoid cystic carcinoma. Recently, the morphologic spectrum was found to be much broader than initially appreciated, including differentiation along multiple cell lines, warranting a nomenclature change to “Human papillomavirus-related multiphenotypic sinonasal carcinoma (HMSC)” [
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
In this case, the patient underwent salvage surgery for recurrence. The process from the initial treatment to recurrence, details of the salvage surgery, and pathological diagnosis are presented. The clinical course of this case and that of previous reports were also discussed. This report provides a better understanding of the disease, which has remained vague due to the limited number of studies.
2. Case report
The patient was a 61-year-old woman with unremarkable medical history and absence of previous/current HPV-related tumors in the patient and family. The patient consulted a previous hospital with a chief complaint of nasal obstruction, and it was discovered that a tumor was located in the left nasal cavity. Biopsy led to the diagnosis of a carcinoma, but no definite histological type could be determined. Computed tomography (CT) showed that the tumor was confined to the left nasal cavity with no metastasis, and it was classified as cT2N0M0(UICC 8th) (Fig. 1). The patient underwent endoscopic resection of the nasal cavity tumor. A nasal septal cartilage correction was performed to widen the surgical field. The tumor was located in the left middle turbinate and did not invade the ethmoid sinus, nasal floor, or nasal septal mucosa. The tumor was large and difficult to remove as a single mass from the nasal cavity; hence, part of the tumor was divided. Postoperative histopathological examination revealed a mixed carcinoma with adenoid cyst-like and squamous cell carcinoma features. The tumor tested diffusely positive for p16 on immunohistochemical staining, leading to the diagnosis of HMSC. The margins were negative, and the patient was followed up without additional treatment. One year and nine months after surgery, the tumor reappeared on the floor of the right nasal cavity, and a biopsy of the same area revealed a local recurrence.
Fig. 1Coronal and axial computed tomography views of sinus following the initial treatment. The tumor is confined to the nasal cavity based on the left middle turbinate.
The patient was referred to our hospital for treatment. CT revealed tumor invasion into the right nasal cavity and hard palate (Fig. 2). There were no metastases, and the tumor was diagnosed as rT3N0M0. Partial maxillectomy, right neck dissection (Level I-III), maxillary reconstruction with the fibula flap, and tracheostomy were performed. Postoperative histopathological examination showed ductal and myoepithelial cells, forming a glandular and cribriform structure, and squamous cell carcinoma components, some of which were stratified and keratinized. The tumor was diffusely positive on p16 immunohistochemical staining (Fig. 3). A DNA sample was extracted from paraffin-embedded blocks of this tumor tissue, and a polymerase chain reaction was performed in which 16 HPV types (6, 11, 16, 18, 30, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66) could be detected and identified in outsource, Primersets (PapiPlexTX) and Thermal Cycler (Takara PCR Thermal Cycler Dice® Standard TP650, Takara Bio Inc.) were used. As a result, HPV type 35 was detected (Fig. 4). The tumor was staged as rpT3N0, ly0, v0, pn0; complete resection was achieved without developing cervical lymph node metastasis. Since the patient had a high risk of local recurrence, radiation therapy (66Gy/33fr) was performed in addition to surgery. After 13 months of treatment, no recurrence or metastasis was observed.
Fig. 2Coronal and axial computed tomography views sinus following local recurrence. The tumor invades the bone and extends into the hard palate, maxillary sinus, and nasal septum.
Fig. 3(A) Hematoxylin and eosin (H&E) staining (10 ×). Histology of the tumor area. (A’) Immunohistochemical staining (10 ×): p16 is diffusely positive. (B) H&E staining (40 ×): Small duct-like structures can be identified in the solid areas. (C) H&E staining (40 ×): Solid components with focal cribriform or tubular patterns and abrupt keratinization within tumor nests.
This study was approved by the Research Ethics Review Committee of our institution (#2020-072). The patient provided informed consent for the publication of the case findings.
3. Discussion
Boland et al. discovered two HPV-positive cases of high-grade adenoid cystic carcinoma [
]. Evocatively, the two HPV-positive tumors demonstrated solid growth and were located in the sinonasal tract. Re-evaluation of sinonasal carcinomas suspected to be “adenoid cystic carcinomas” led to the detection of additional cases [
Human papillomavirus-related carcinoma with adenoid cystic-like features: a peculiar variant of head and neck cancer restricted to the sinonasal tract.
Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases.
]. Based on a total of nine cases, this distinctive sinonasal tumor was included in the 2017 WHO Classification of Head and Neck Tumors as a “provisional” tumor entity under the designation “HPV-related sinonasal carcinoma with adenoid cystic-like features” [
]. Based on the contributions from various head and neck pathology consultation practices, the morphologic spectrum was much broader than initially appreciated, including differentiation along multiple cell lines, warranting a nomenclature change to the more capacious “HPV-related multiphenotypic sinonasal carcinoma (HMSC)” [
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
Human papillomavirus-related carcinoma with adenoid cystic-like features: a peculiar variant of head and neck cancer restricted to the sinonasal tract.
Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases.
The histology of this tumor resembles that of adenoid cystic carcinoma, consisting of solid and cribriform structures of uniform basaloid cells. Small duct-like structures were observed in the solid areas. It is characterized by a dual population of myoepithelial cells, positive for calponin, p63, action, and S100, surrounded by a population of c-kit-positive ductal cells on immunohistochemistry; the p16 was diffusely positive. Its other distinguishing characteristics include the absence of MYB gene rearrangements and the presence of high-risk HPV. HPV types 16, 33, 35, and 56 have been reported, with type 33 being the most common [
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
]. Furthermore, HPV in situ hybridization (ISH) provides strong evidence that the tumor is HPV-driven. We were able to confirm the presence of HPV type 35, but were unable to perform ISH due to cost constraints.
Pathological diagnosis needs to be differentiated from SMARCB1-deficient sinonasal carcinoma, biphenotypic sinonasal sarcoma, and renal cell-like adenocarcinoma. SMARCB1-deficient sinonasal carcinoma is a highly aggressive carcinoma histologically composed of infiltrating nests of relatively uniform basaloid cells, but at least some elements have abundant, eccentric, eosinophilic cytoplasm, imparting a rhabdoid appearance [
]. Renal cell-like adenocarcinoma has a distinctive histologic appearance, composed of a uniform population of cuboidal-to-columnar cells with glycogen-rich clear cytoplasm without mucin production [
]. Biphenotypic sinonasal sarcoma has distinctive histologic features, including a bland, spindle cell proliferation arranged in fascicles below an intact, proliferative surface epithelium [
]. This case does not have any of these histological features.
The clinical behavior is more common in women than men. Reportedly, diagnoses in patients with ages ranging from 28 to 90 years old have occurred. The nasal cavity, paranasal sinuses, middle turbine, and nasal septum are the most common sites of occurrence [
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
]. There is currently no gold standard or consensus treatment. Most patients are surgically treated with or without adjuvant chemotherapy or radiotherapy. Previously, in most large case series, 14 out of 39 (36%) patients developed local recurrences [
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
]. For initial treatment, 18 patients underwent surgical resection alone, 15 patients received surgery with postoperative radiation therapy, 3 patients underwent surgery followed by chemoradiation, and 3 patients received chemoradiation without surgery. The length of follow-up ranged from 1 to 256 months (mean, 42 months). In addition to the recurrence rate, it is important to highlight the length of the disease-free interval between primary treatment and local recurrence. Although 43% of the patients in that series presented with an advanced tumor stage, none developed lymph node metastasis or died from the disease. This suggested the more indolent clinical behavior of the disease than other sinonasal carcinomas. There is also no consensus on postoperative radiation therapy. However, recent reports indicated that adjuvant radiation therapy did not impact long-term survival but increased the disease-free interval [
The clinical course of this case was also consistent with those of previous reports, with a long interval between surgical treatment and recurrence (1 year and 9 months). Furthermore, in the present case, the primary tumor of the left sinonasal cavity was initially resectable with negative margins but recurred with an invasion of the right nasal floor and nasal septum. It is possible that the tumor remained in the nasal cavity because it was not removed as a single mass. In addition, the left and right nasal cavities were open due to nasal septoplasty. The narrow nasal cavity was in contact with the tumor; thus, the tumor might have disseminated. This patient underwent salvage surgery and postoperative radiotherapy. Recurrence has not been observed for up to 13 months. According to previous reports, the disease has a favorable prognosis but a high local recurrence rate. Therefore, long-term follow-up is necessary.
4. Conclusions
HMSC is a rare primary tumor of the sinonasal tract that has been reported recently. More studies, including large cohorts and long-term follow-up, are required to better understand the clinical nature of this entity.
Disclosure statement
The authors declare no financial disclosures or conflicts of interest.
Funding statement
None.
Acknowledgment
We would like to thank Kazuhiro Omura, MD, Jikei University School of Medicine otorhinolaryngology for support in writing.
References
Singhi AD
Westra WH.
Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience.
HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features.
Human papillomavirus-related carcinoma with adenoid cystic-like features: a peculiar variant of head and neck cancer restricted to the sinonasal tract.
Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases.
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