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Oncocytic Schneiderian papilloma-associated adenocarcinoma and KRAS mutation

Abstract Rationale: Oncocytic Schneiderian papillomas (OSP) are an uncommon type of sinonasal papillomas that arise from the Schneiderian epithelium, accounting for only 6% of all sinonasal papillomas. Malignancies arising in OSP are rare and are almost always described as in situ or invasive squamous cell carcinoma, although mucoepidermoid, small cell carcinoma and sinonasal undifferentiated carcinoma have also been reported. To our knowledge, only 18 such instances have been reported in the medical literature. Patient concerns: Here, we report the case of an 81-year-old man presenting with a left sinonasal neoplasm, who had undergone 4 operations. The first postoperative pathology revealed a benign nasal polyp. The following several postoperative pathology revealed a novel, human papillomavirus-negative adenocarcinoma with increasing malignant features with each recurrence arising in an OSP. In addition, the most recent recurrences were associated with metastasis of cervical lymph nodes. And after the operation, the patient refused adjuvant radiotherapy. On 6-month follow-up after the last operation, the patient developed an in situ tumor recurrence 1 month after the fourth operation and refused to undergo surgery again. Diagnosis: Immunohistochemistry for Ki67, CK7, CK5/6, P53, and P63 showed a progression of malignancy. HPV assay presented the 21 most prevalent HPV types were negative. In addition, KRAS gene exon 2 G12C presented mutation in the OSP-associated adenocarcinoma. Interventions: During the whole course of the patient's disease, we performed four nasal endoscopic operations. And after the last operation, the patient refused adjuvant radiotherapy and KRAS-targeted therapy. Outcomes: We are the first to describe adenocarcinoma arising in an OSP. To our surprise, from the first benign neoplasm to the second OSP-associated adenocarcinoma, it went through a long period of 10 years. However, after the adenocarcinogenesis, the differentiation of tumor became worse with the shorter interval of each recurrence. Lessons: Therefore, for elderly patients with unilateral nasal polyps, long-term follow-up is necessary. Once OSP turns into malignant, radical resection should be performed as much as possible to reduce the irritability of tumors.


Introduction
Schneiderian papillomas are uncommon benign neoplasms derived from the Schneiderian epithelium, which is an ectodermally derived ciliated respiratory epithelium that covers the surface of the nasal cavity and paranasal sinuses. These tumors account for approximately 0.4% to 4.7% of sinonasal tumors. [1] The World Health Organization (WHO) defines 3 types of Schneiderian papillomas: exophytic papillomas (EP), inverted papillomas (IP), and oncocytic Schneiderian papillomas (OSP). The morbidities of the 3 types of papillomas are quite different. [2,3] Hyams [4] reported the proportion of these tumors as EP 49.5% and IP 47.3%, and OSP 3.2%. OSPs are the rarest of the 3 subtypes. [2] Human papillomavirus (HPV) can be found in IP and EP, but not in OSP. [5,6] Therefore, OSP is considered to have a different pathogenesis, although the initial clinical manifestations are similar. All 3 types can progress to carcinoma, especially IP and OSP. The most common type of carcinogenesis in Schneiderian papillomas is squamous cell carcinoma, [7] and there are also reports of mucoepidermoid carcinoma, small cell carcinoma, and sinonasal undifferentiated carcinoma. [3,7,8] Some reports have estimated a prevalence of carcinoma development in as high as 10% to 15% of IP cases. [9] OSP also has a risk for malignancy, but malignancies arising in OSPs are rare, with invasive squamous cell carcinoma being the most frequently reported tumor, [4,[10][11][12] Given the rarity of these cases, the true rate of malignancy is hard to assess. [10] To the best of our knowledge, only 18 such instances (Table 1) have been reported in the medical literature. [13][14][15] To date, there is no report on adenocarcinoma arising in the papillomas of the nasal cavity and paranasal sinus. Also, there are few reports on the biological behavior of OSP-related tumors after malignant transformation, such as in recurrence, lymph node metastasis, and distant metastasis. [14] Only 1 case described cervical lymph node metastasis after carcinoma arising in IP. [14] To our knowledge, metastasis following malignant transformation arising in OSP and the progress of the disease have not yet been reported.
Pathological diagnosis is the criterion standard for diagnosis and plays a vital role in the treatment and prognosis of Schneiderian papillomas. For patients with multiple surgeries and recurrences, dynamic observation of the pathological changes is helpful to guide treatment decisions.
Here, we report a longitudinal study on a patient with OSPrelated adenocarcinoma who required multiple surgeries and allowed for analysis of the recurrent pathology. Combining clinical phenotypes with pathological characteristics and genotypes helped provide guidance for diagnosis and treatment for this case.

Ethics review and patient consent
This case report dealt only with the patient's clinical records. Ethics committee approval was not thought to be necessary because the entire clinical course of the case was within standard medical care. Informed consent on diagnosis and treatment was given by the patient.

Patient
A 69-year-old Chinese man presented in 2005 with left nasal obstruction and occasional epistaxis after a cold to the Otolaryngology clinic at the Peking University People's Hospital of China, a tertiary care academic center in Beijing, China. He denied rhinorrhea, headaches, and ophthalmic or neurological symptoms. His medical history was remarkable for hypertension and coronary heart disease. Endoscopic examination revealed a large left sinonasal mass, and imaging confirmed the absence of bony erosion into the orbit or skull base. We performed endoscopic extirpation of the left nasal polyp under local anesthesia. Postoperative pathology revealed a benign nasal polyp.
At the age of 79 years (in 2015), the patient presented with similar symptoms at Beijing Tongren Hospital, Beijing. Physical examination revealed the presence of a polyploid mass partially filling the middle meatus with extension into the nasal cavity. Computed tomography (CT) and magnetic resonance imaging (MRI) examination of the paranasal sinus ( Fig. 1) revealed unilateral maxillary sinus disease, left orbital suborbital nerve canal hyperostosis, and findings consistent with inverted papilloma. Endoscopic sinus surgery was performed under general anesthesia. Intraoperative frozen pathology revealed carcinoma arising in inverted papilloma. The hyperostosis of the suborbital nerve canal of the maxillary sinus was removed and the margins of resection ended up positive. However, postoperative permanent pathology demonstrated carcinoma arising in OSP. The patient was recommended to have radiotherapy for the primary site of the tumor, but he declined.
The patient presented at age 81 years (in 2017) to Anzhen Hospital in Beijing with similar obstructive symptoms. CT and MRI ( Fig. 1) revealed inflammatory response of the left maxillary bone and a space occupying lesion of the left nasal cavity. A soft tissue density mass was found in the left nasal cavity and sinus, with absence of bony erosion into the orbit or skull base. Endoscopic sinus surgery with surgical navigation under general anesthesia was performed with complete removal of the tumor and negative margins by frozen section. Postoperative histopathology was high-grade nonintestinal adenocarcinoma. The patient still refused to undergo radiotherapy after surgery.
After 5 months, the patient returned and physical examination showed a neoplasm in the left nasal cavity, with a rough surface, easy bleeding, and purulent secretions on the surface of the tumor. In addition, there were palpable enlarged, hard, immbolile submandibular lymph nodes on that side (2.2 Â 2.0 Â 1.8 cm). CT, MRI, enhanced MRI (Fig. 1), and positron emission tomography-computed tomogramphy (Fig. 2) were performed and revealed 2 masses in the nasal cavity. One was located at the Table 1 Malignancies Arising in Oncocytic Schneiderian Papillomas.

Reference
Year Cases Histology Hyams [4] 1971 1 Squamous cell carcinoma Barnes and Bedetti [11] 1984 1 Mucoepidermoid carcinoma Ward et al [8] 1990 1 Squamous cell carcinoma Ward et al [8] 1990 1 Papillary transitional carcinoma Kapadia et al [10] 1993 6 Squamous cell carcinoma Kapadia et al [10] 1993 2 Mucoepidermoid carcinoma Kapadia et al [10] 1993 1 Sinonasal undifferentiated carcinoma Yang and Abraham [12] 1997 1 Sinonasal undifferentiated carcinoma Maitra et al [13] 2001 1 Sinonasal undifferentiated carcinoma Maitra et al [13] 2001 1 Small cell carcinoma Kaufman et al [15] 2002 1 Squamous cell carcinoma Lewis et al [14] 2015 1 Papillary Schneiderian carcinoma    with negative frozen margins. We also performed a selective left neck dissection. Postoperative pathology of the primary tumor was low-differentiated adenocarcinoma and we found metastatic adenocarcinoma with low-differentiation in the cervical lymph nodes. The patient disagreed to receive adjuvant radiotherapy and targeted drug therapy for KRAS gene. During 6 months' follow-up after the last operation, the patient developed an in situ tumor recurrence 1 month after the fourth operation and refused to undergo surgery again.

Tissue preparation
Pathological sections were collected from all 3 hospitals after 3 operations, including the primary site and the metastatic lymph nodes. All diagnoses were confirmed centrally by an experienced head and neck pathologist (JBM).

Immunohistochemistry
Immunohistochemical studies were performed on 4-mm thick paraffin sections according to routine protocols using the EnVision method. The antibodies used for analyses are listed in Table 2. All antibodies were monoclonal; heat-induced epitope retrieval was performed by heating in Tris-EDTA buffer, pH 9.0. Immunostaining was reviewed by a single pathologist. Results were considered positive when >30% of tumor cells were stained.

HPV assay
The BioPerfectus Multiplex Real Time (BMRT) HPV assay (Bioperfectus Limited Corp., TaiZhou, China) was developed to detect 13 high-risk (HR) HPV types, 5 medium-risk (MR) types, and 3 low-risk (LR) HPV types, as well as the viral loads simultaneously. PCR primers and corresponding TaqMan probes were designed to detect each of the 21 most prevalent HPV types,

Pathologic findings and immunohistochemical features
At the first resection, there was a pathological diagnosis of nasal polyps; unfortunately, these slides could not be found for analyses. At the second resection (Fig. 3), part of the tumor tissue supported the diagnosis of OSP, displaying a papillary structure and oncocytic appearance under low magnification. Observation under medium magnification showed that the microabscess structure was constructed by neutrophils and the cells were arranged orderly, and there were no heteromorphic features. Scattered mucous-secreting cells and small cavities were visible under high magnification, and the cells were not heterotypic. The tumor consisted of a bland, papillary, and inverted neoplasm. The cells had abundant, eosinophilic cytoplasm. Mitotic activity, however, was low in this area. The proliferation index was low and the basal layer cells were positive, indicating that the growth of the tumor was slow. There was no significant apoptosis and there was no necrosis. Immunohistochemical staining for p53 was positive only in the basal layer, indicating that the cells were benign.
However, another part of the tumor tissue supported the diagnosis of adenocarcinoma arising in OSP. At low magnification, the papillary structure was displayed in a small cluster. The cells were crowded and the layered structure was absent. Obvious cell atypia and the nucleoli were clearly visible under medium magnification. Under high magnification, the cells were crowded and disorderly, and the cells were heteromorphic. In addition to the papillary structure, infiltration of the gland tubular structure was visible in the interstitium. There was significant apoptosis and necrosis in this area. Mitotic activity, however, was high in this resected specimen. Immunohistochemistry for Ki67 showed a progression of staining across the 2 areas and an increase in mitotic activity. Immunohistochemical staining for p53 was positive. The overall pathological analysis of the resected tumor tissue showed that the lesions conformed to OSP. The formation and development of adenocarcinoma could be seen in some areas at the same time.
At the third resection, observation under low magnification showed the structure of the nipple and crowding of the cells. At medium magnification, the cell levels were increased; the cells were crowded and the cells were obviously heterotypic (Fig. 4).  Immunohistochemistry for CK5/6 and p63 was negative, but CK7 staining was positive. Thus, the tumor was adenocarcinoma, not squamous cell carcinoma. At the fourth resection (Fig. 5), low magnification images revealed interstitial infiltration of the gland ducts and the fibrous connective tissue around the ducts. In some regions, there was a solid arrangement of tumor cells and a lowdifferentiated carcinoma structure. There was obvious cell atypia under high magnification. Immunohistochemistry for CK5/6 and p63 was negative and staining for CK7 was positive. Immunohistochemistry for Ki67 showed that the proliferation index was high and the cancer cells were actively proliferating.
In analyzing the pathological changes, we found that the patient developed high-differentiated adenocarcinoma from OSP at first, and then moderately differentiated adenocarcinoma, and finally poorly differentiated or undifferentiated carcinoma. The entire process occurred over 3 years, and the recurrence interval was shorter over time, with an eventual appearance of lymph node metastasis.

HPV phenotypes
Both the initial resection specimen and the late course lymph node metastasis were negative for the 21 most prevalent HPV types.

Discussion
Schneiderian papillomas are not common and OSPs are even more rare. IPs and OSPs are associated with a low risk for malignancy, of approximately 5% to 10%. [4,8,11,12,[15][16][17][18] This is well established and is reported to occur through the progression of squamous metaplasia to squamous dysplasia and then carcinoma. [2,7] However, no definite case of adenocarcinoma with increasing malignant features arising from OSPs has been reported to date.
Here, we present a case of adenocarcinoma arising from OSP, according to pathological review. A papilloma is classified as OSP based on the presence of an epithelium composed of multiple layers of tall, columnar oncocytic epithelium with both exophytic and inverted growth patterns, up to 2 to 8 cells thick. The pathological features of OSP include cells with abundant, eosinophilic cytoplasm and intraepithelial microabscess that contains mucus and neutrophils. [3,11] In the second relapse of the tumor in the present case, a typical feature of OSP was found in some areas by microscopy. In some areas, except for the papillary structure, there was an infiltration of an adenoid tube structure in www.md-journal.com the stroma, and pathological mitosis, necrosis, and nuclear fragmentation were observed. Combined with clinical and pathological features, this suggests that synchronous adenocarcinoma was arising from OSP. These were not 2 independent diseases. In addition, the degree of malignancy in the adenocarcinoma changed over recurrence and surgery. The initial features described here were not typical for any defined Schneiderian papilloma and this case was misdiagnosed as a nasal polyp. This suggests that we should take multiple biopsies for intraoperative frozen pathological examination for unilateral polypoid lesions to prevent misdiagnosis. The relative rarity of OSP prevents comparison between OSP and IPs for local recurrence and malignancy coexistence. [19] Here, we find that OSP is similar to IP by reviewing the clinical and radiological characteristics of this disease. For example, the lesions are located in unilateral sinus, with a pale pink appearance. Also, the hyperplasia of bone at the root of the tumor was detected by CT and via MRI. The second recurrence was diagnosed as oncocytic papilloma and concurrent with adenocarcinoma according to the final pathology. However, at that time, clinical and intraoperative frozen pathological results supported IP. The tumor recurred 4 times over 13 years, despite extensive surgical resection, including removal of the vertical plate of palatine bone, root of pterygoid muscle, and lymph node neck dissection.
Throughout the patient's entire clinical course, the malignant features of the tumor were increasing, which manifested in the shorter time interval of recurrence, increased mitotic activity, and lymph node metastases.
In particular, regarding the pathological features of the third relapse, if no previous pathological analysis had been available, it would have been difficult to make an accurate diagnosis from only these results. As with all complex cases and recurrences, a diagnosis should consider previous pathology results; this is often a challenge, especially for this patient who was treated at 3 different centers.
The exact relationship between HPV and the pathogenesis of papillomas, along with malignant transformations, is not clear. The literature shows that low-risk and high-risk HPV can be found in a significant minority of IPs (usually high-risk HPV types) and the majority of EP (usually low-risk HPV types). [5] However, low-risk and high-risk HPV has not been found in OSP. [5] Both the initial resection specimen and the late course lymph node metastasis from this rare case were also HPVnegative.
Highly prevalent activating EGFR mutations were identified in the vast majority of IP cases and also are commonly present in ISP-associated sinonasal squamous cell carcinoma but not in ESP, OSP, or sinonasal squamous cell carcinoma without a known Medicine papilloma association. [20] Some studies have indicated that KRAS mutations may be a disease-defining molecular feature of sinonasal oncocytic tumors. [21] In this case report, KRAS mutations were found in the OSP-associated adenocarcinoma. The presence of KRAS mutations in this tumor indicates that EGFR-targeted therapy is likely to be ineffective.

Conclusions
This is the first case of adenocarcinoma of nasal cavity and paranasal sinuses with increasing malignant features arising from OSP in the literature to our knowledge. The tumor ultimately invaded deep soft tissues, with a 13-year period of progressive disease recurrence with lymph node metastases. This tumor appears to represent a unique type of sinonasal adenocarcinoma, which is associated with OSP. This patient illustrates the idea that progression from OSP to OSP-associated adenocarcinoma may take years, but once OSP has been transformed into adenocarcinoma, it shows increasing malignant features. This is also the first report of somatic KRAS mutation in OSP-associated adenocarcinoma. KRAS-targeted therapy may play a therapeutic role in the treatment of this rare disease.