Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall

Highlights • A very rare type of benign sinonasal polyps.• Potential misdiagnosis as malignancy.• Immunohistochemical stains are very contributive to diagnosis.


Introduction
Sinonasal polyps are morphologically classified into five types ---edematous, fibrous, glandular, cystic and angiectatic. 1 Angiectatic Nasal Polyp (ANP), also known as angiomatous polyps, is a very rare type of sinonasal polyps. Angiectatic Nasal Polyp with Pleomorphism (PANP) are benign lesions of nose and paranasal sinuses, 2 characterized by hemorrhage and necrosis, occasionally accompanied by bizarre large pleomorphic spindle cells hyperplasia. Clinically, it grows rapidly and exhibits an aggressive clinical behavior, simulating malignancy. 3---6 In spite of its characteristic findings on imaging, however, it is radiologically challenging to pick it up. Therefore, histopathology features are essential for making definitive diagnosis.
In this report, we identified and summarized the features of thirteen patients with PANP from clinical manifestations, imaging, and histopathology. Awareness of these features would be helpful to avoid misdiagnosis and unnecessary treatment.

Ethical justification
The study was approved by the Ethical Committee of the Department of Pathology in Beijing Tongren Hospital affiliated to Capital Medical University. We retrospectively analyzed thirteen patients diagnosed as PANP in the Department of Pathology in Beijing Tongren Hospital affiliated to Capital Medical University from August 2014 to December 2019. Clinical data are summarized in Table 1.

Methods
Histology tissue samples were fixed with 10% neutral formaldehyde, dehydrated with ethanol and embedded in paraffin. 4 m thick sections were prepared and stained with Hematoxylin-Eosin Staining (HE) and Immunohistochemistry (IHC) staining method. The sections were observed under B ×50 microscope of Olympus.

Hematoxylin-eosin (HE) staining
4 m sections were obtained from each paraffin block using a microtome (Thermo Scientific, MICROM HM 340E, America) and stained with HE. Samples were de-waxed in two changes of xylene (5 min each), rehydrated to water with graded alcohols and stained with hematoxylin for 5 min. After rinsing the sections in water, the hematoxylins were differentiated in 1% hydrochloric acid in 70% ethanol. Sec-tions were stained with eosin for 3 min, re-immersed in alcohol and xylene, dehydrated in ethanol, cleared in xylene and cover slipped in a resinous mountant.
Tissue sections were deparaffinized and rehydrated. Antigen retrieval was achieved by pressure cooking in 0.1 M citrate buffer, Ph 6, for 10 min followed by cooling at room temperature before incubation with the antibodies. Sections were pre-incubated with 3% hydrogen peroxide at room temperature for 10 min so as to block nonspecific antibody binding. Subsequently, the sections were incubated overnight at 4 • C with specific primary antibodies followed by horseradish peroxidase-linked sheep anti-mouse/rabbit secondary antibody (Origene, America) for 60 min. Controls were carried out by omitting the first antibody. The reactions were visualized by 3, 3-Diaminobenzidine (DAB). The slides were then counterstained with hematoxylin. Slides were mounted using a synthetic resin.

Clinical presentation
The average age of thirteen patients with PANP was 20.8 (range 7---58), median age was 13. The gender ratio was 10:3 (male to female) (Details in Table 1). Patients presented nasal obstruction, snoring, headaches, toothache, orbital pain and/or facial pain. Office endoscopic examination revealed a large polypoid mass in the nasal cavity and paranasal sinuses. The mass had an unusual inhomogenous appearance (Fig. 1). Computed Tomography (CT) demonstrated a soft tissue-density mass, with bone discontinuity usually. Magnetic Resonance Imaging (MRI) showed the mass with hypointensity on T1-weighted images and hyperintensity intensity on T2-weighted images.The mass showed markedly heterogeneous enhancement after contrast material administration (Fig. 2).

Histologic features
Thirteen cases of PANP were composed of variegated tan to gray soft fleshy tissue, while accompanied by obvious Runny nose for two years, stuffy nose for more than one month, with headache, severe on the right.
CT showed soft tissue shadow in the right nasal cavity and paranasal sinus, which involved local bone of the right maxillary sinus.
Postoperative recovery   hemorrhage and necrosis. Their stroma was edematous and loose mucoid composed of enlarged and pleomorphic cells with atypical hyperchromatic nucleus. Obvious dilated vascular components, sometimes accompanied by hemorrhage, thrombosis and infarction were also seen in the interstitum. The deposition of pink staining and amorphous protein like substance were present occasionally (Fig. 3).

Immunohistochemistry
As summarized in Table 2, immunohistochemistry stain is another valuable method to diagnosis. Vimentin (Vim) stain was consistently positive, while negative for CD34 and STAT-6. Calponin stain was positive in nine cases. CK stain was positive in nine cases. Bcl-2 stain was focal positive in two cases. All cases showed low Ki67 positive indexes (Table 2).

Discussion
Angiectatic Nasal Polyp (ANP), a rare inflammatory sinonasal polyp, often develops secondary to changes in choanal polyp. It is vulnerable to vascular compromise in specific sites, such as ostium, posterior end of the inferior turbinate, choana and nasopharynx. 2,7,8 Nasal obstruction is the most common symptom, followed by decrease or loss of smell perception, epistaxis, proptosis and visual disturbances. 2,7---9 PANP is an exceedingly rare subtype of ANP. The course of the disease is long, the progress is slow, and the bone is swelling rather than erosive destruction. It is often unilateral, manifested as runny blood or epistaxis and accompanied by swelling destruction of the bone wall of the paranasal sinuses. Histologically, it is characterized by extensive vascular proliferation and dilation with Congo red negative pseudoamyloid material deposition. 7 Shobha et al. found racemose aggregates of irregularly shaped blood vessels resembling dilated capillaries without elastic or muscular layers, accompanied by patchy necrosis and atypical stromal spindle cells. 3,10,11 Electron microscopy and immunohistochemistry (CD34, factor VIII) results show endothelial cells lining the spaces and myofibroblasts in interstitium. 2 On the MRI scan, T2-weighted images show internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. 12,13 Vessel-like marked and progressive enhancement are important features on 2phase helical CT scan. It is often associated with a soft tissue mass shadow of uneven density, with stripped and nodular high-density shadow located around and inside the lesion. The adjacent bone, especially the inner wall of maxillary sinus, shows discontinuous compression and absorption changes.
Given the manifestations of imaging and pathology, the diagnosis of PANP is still difficult because of potential confusion with Pleomorphic Hyalinizing Angiectatic Tumor (PHAT). PHAT is one of the low-grade intermediate ---locally aggressive soft tissue mesenchymal tumors with undetermined tissue differentiation. 14 It mainly occurs in adults and is classified as undetermined differentiation tumors in soft tissue and bone tumors by WHO in 2020. 15 Smith et al. first described its morphology, which is characterized by the expanded hyaline degeneration of the cluster thin-walled vessels, and pleomorphic spindle shaped and oval shaped pleomorphic cells in interstitium. 16 It is extremely rare and easily misdiagnosed since the morphology is similar to that of PANP. A large number of dilated thin-walled blood vessels are distributed in clusters, with different lumen sizes. Pink staining and amorphous protein like substance can be seen under the intima of the vessels. Hyaline degeneration can be seen on the wall of the vessels, extending from the vessels to the interstitium around the vessels. Organized and recanalized thrombus can be seen in some vessels. Pleomorphic tumor cells are interspersed between blood vessels in sheet or bundle shape. The tumor cells are spindle, round or oval, with pleomorphic nuclei. Giant cells of pleomorphic tumor can be seen, but mitosis is rare. It is a characteristic histological change, with pseudoinclusions in the nucleus. Erbolat KQ et al. thought that vimentin and CD34 17,18 were positive in PHAT tumor cells, were positive in some of them, and low Ki67 PI suggested that tumor cells had low proliferative activity (<5%). 19 Imaging findings showed that surrounding bone were damaged, sometimes discontinuously, in both. However, histological examination showed that PHAT appeared to contain more hyalinized and degenerated thin-walled dilated blood vessels and marked stomal atypia, which was helpful for distinguishing.
Complete removal of PANP lesions by operation is the only effective treatment method, and the prognosis is good. On the contrary, PHAT is an intermediate ---locally aggressive soft tissue tumor with high recurrence rate. Therefore, extend local resection and long-term followup are recommended. In summary, understanding the clinical manifestations, imaging and pathological features are essential for making proper diagnosis and treatments between the two diseases in the nasal cavity and sinuses.

Conclusion
PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment.

Funding
There is no funding for this work.

Conflicts of interest
The author declares no conflicts of interest.