Nasal cavity, paranasal sinuses, nasopharynx

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Authors: Surekha Bantumilli, M.D., Margaret S. Brandwein-Weber, M.D., Josephine K. Dermawan, M.D., Ph.D., Rimlee Dutta, M.B.B.S., M.D., Jesse Hart, D.O., Vladyslav Ilchenko, M.D., Saira Javeed, M.B.B.S., M.Phil., Jinping Lai, M.D., Ph.D., Kelly Magliocca, D.D.S., M.P.H., Rifat Mannan, M.B.B.S., M.D., Susan Maygarden, M.D., Arun R. Napit, M.B.B.S., Nat Pernick, M.D., Madiha Bilal Qureshi, M.B.B.S., Laura O. Rabinowitz, M.D., Lisa Rooper, M.D., Abeer Salama, M.D., Jihong Sun, M.D., Wai Szeto, M.D., M.S., Abhimanyu Tushir, M.D., Nasir Ud Din, M.B.B.S., Bin Xu, M.D., Ph.D., Songyang Yuan, M.D., Ph.D.

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Adenocarcinoma-general Allergic fungal sinusitis Allergic rhinosinusitis Anatomy Antrochoanal polyps Biphenotypic sinonasal sarcoma Chordoma Chronic rhinosinusitis Fungal ball Glial heterotopia Grossing & features to report Hairy polyp High grade neuroendocrine carcinoma Histology HPV related multiphenotypic sinonasal carcinoma Inflammatory sinonasal polyp Intestinal type Invasive fungal rhinosinusitis Low grade nasopharyngeal papillary adenocarcinoma Nasal chondromesenchymal hamartoma Nasopharyngeal angiofibroma Nasopharyngeal carcinoma Nonintestinal type NUT carcinoma Olfactory neuroblastoma Respiratory epithelial adenomatoid hamartoma Rhinosclerosis Rhinosporidiosis Salivary gland anlage tumor Seromucinous hamartoma Sinonasal carcinoma-general Sinonasal glomangiopericytoma Sinonasal lymphoepithelial carcinoma (pending) Sinonasal papilloma Sinonasal undifferentiated carcinoma Squamous cell carcinoma Staging terminology Staging-nasal cavity & sinuses Staging-nasopharynx SWI / SNF complex deficient sinonasal carcinoma Teratocarcinosarcoma WHO classification

Adenocarcinoma-general

Table of Contents

Definition / general

Sinonasal adenocarcinoma (SNAC) is a relatively rare and heterogenous type of carcinoma of the sinonasal region (i.e., the nasal cavity and paranasal sinuses) with glandular differentiation
May originate from respiratory surface epithelium or the underlying seromucinous glands (Head Neck Pathol 2016;10:68)

Essential features

Rare type of carcinoma originating from the sinonasal area (nasal cavity and paranasal sinuses)
On histology, the tumor resembles adenocarcinoma that arises at other body locations
Several histologic tumor subtypes are described
Adequate surgical resection is the usual treatment but has poor prognosis

ICD coding

ICD-O:
- 8140/3 - adenocarcinoma, NOS
- 8144/3 - intestinal type adenocarcinoma
ICD-11:
- 2C20.0 & XH0349 - adenocarcinoma of nasal cavity & adenocarcinoma, intestinal type
- 2C22.0 & XH0349 - adenocarcinoma of accessory sinuses & adenocarcinoma, intestinal type
- 2C20.0 & XH74S1 - adenocarcinoma of nasal cavity & adenocarcinoma, NOS
- 2C22.0 & XH74S1 - adenocarcinoma of paranasal sinuses & adenocarcinoma, NOS

Epidemiology

Second most common malignancy of the sinonasal region, after squamous cell carcinoma, comprising 10 - 20% of primary sinonasal malignancies (Acta Otolaryngol 2018;138:415)
Average age of presentation is between 50 and 60 years (Nat Rev Clin Oncol 2014;11:460)
Higher incidence in Europe compared to North America, while less is known about the incidence in Asia, Africa, Oceania and South America (J Neurooncol 2020;150:405)
Higher incidence in men compared to women (up to 6:1 in ITAC), probably due to occupational hazards (Nat Rev Clin Oncol 2014;11:460)

Sites

Intestinal type adenocarcinoma (ITAC) is most often localized in the ethmoid sinus (40%), followed by the nasal cavity (25%) and the maxillary antrum (20%)
ITAC associated with wood dust exposure occurs predominantly in the ethmoid sinus, while sporadic ITAC often arises in the maxillary sinus
Due to their aggressive nature, ITAC may spread to adjacent structures, including the orbit, the pterygopalatine fossa, the infratemporal fossa and the cranial cavity
Low grade nonintestinal type adenocarcinomas are uncommon and occur mainly in the ethmoid sinus, the nasal cavity and the maxillary sinuses (Head Neck Pathol 2016;10:68)

Etiology

Occupational exposure to wood dust (furniture), leather (shoe production), chromium and nickel
Large particle dust from certain hardwoods (ebony, oak and beech) is thought to provide a 900 fold risk of developing adenocarcinoma (Am J Rhinol Allergy 2013;27:S35)
Cumulative exposure time to wood dust in patients with ITAC has been 40 - 43 years (Head Neck Pathol 2016;10:68)
< 5 years of exposure is still considered critical and the latency to tumor development is delayed (~40 years)
Other significant etiologic associations include
- Alcohol and cigarette smoking (Head Neck 2014;36:1490)
- Formaldehyde (Cancer Causes Control 2002;13:147)
- Leather dust (Acta Otorhinolaryngol Ital 2004;24:199)

Clinical features

Usually nonspecific clinical findings that mimic benign conditions, including rhinorrhea, nasal obstruction, epistaxis and hyposmia, highlight the importance of initial clinical suspicion
Regional symptoms such as neck lumps, orbital changes (proptosis), diplopia, epiphora and cranial nerve dysfunction are relatively uncommon for most subtypes and are seen in advanced stage tumor (Nat Rev Clin Oncol 2014;11:460)
Visible morphologic changes to hard palate mucosa or overlying skin are rarely seen (Am J Rhinol Allergy 2013;27:S35)

Diagnosis

Often delayed due to location and nonspecific symptoms (Otolaryngol Clin North Am 2004;37:473)
Most patients will undergo both computed tomography (CT) and magnetic resonance imaging (MRI) to obtain precise anatomical details regarding the tumor localization and extension (staging), which are critical in determining operability or in planning radiotherapy (Nat Rev Clin Oncol 2014;11:460)
Endoscopic guided biopsy under local anesthesia for histologic confirmation
If a deep biopsy is required or if profuse bleeding is anticipated, the procedure is performed in an operating room under general anesthesia
Nonintestinal type adenocarcinoma (non-ITAC) is a diagnosis of exclusion (J Neurooncol 2020;150:405)

Radiology description

Presents as an ill defined and heterogeneously enhancing mass in the sinonasal cavity or area in the base of the skull
Bone involvement is shown by CT scan as an aggressive pattern of bone erosion invading surrounding structures
Soft tissue details are seen in MRI findings
PET CT scan defines the regional and distant metastasis; an efficient tool for tumor staging (Am J Rhinol Allergy 2013;27:S35)

Radiology images

Images hosted on other servers:

Large right nasal cavity mass

Contrast CT of a soft tissue mass

MRI with gadolinium showing an enhancing mass

Prognostic factors

ITAC: usually advanced disease at presentation, poor prognosis with a 5 year survival rate of ~60% depending upon disease extent (local extension and metastasis) and histologic type
Low grade non-ITAC: overall favorable outcome; usually localized but the possibility of localized recurrence, metastasis is unusual, death is rare
High grade non-ITAC: poor prognosis (Head Neck Pathol 2016;10:68)
High grade, signet ring cell morphology and local invasion have a worse prognosis

Case reports

26 year old man presented with 3 - 4 months of epistaxis, bilateral nasal obstruction, hyposmia and headaches (Cureus 2021;13:e14285)
29 year old woman was referred for a posterior choanal mass (Ear Nose Throat J 2022 Aug 10 [Epub ahead of print])
44 year old man, without exposure to wood dust, presented with left nasal discharge and obstruction and left sided headache (South Asian J Cancer 2020;9:183)
45 year old man who was a chronic smoker presented with an isolated retro-orbital headache, resistant to analgesics (Pan Afr Med J 2014;18:284)
81 year old man who was formerly a carpenter presented with unilateral deteriorating vision (Ugeskr Laeger 2018;180:V12170942)
84 year old male nonsmoker and nondrinker complained of nasal fullness (Ann Ital Chir 2016;87:S2239253X16025019)

Treatment

Adequate surgical resection is the usual treatment
Surgery followed by radiotherapy for advanced stage disease or if there is a possibility of recurrence
Radiotherapy or combined chemoradiotherapy may be an alternative to definitive surgery for a nonsurgical candidate
Reference: J Neurol Surg B Skull Base 2020;81:627

Clinical images

Images hosted on other servers:

Painless, soft mass on the glabellar region

Gray-white polypoidal mass in right nostril

Gross description

Polypoidal, fungating, nodular or papillary mass
Usually friable, with ulceration and hemorrhage
Rarely gelatinous or mucoid
Reference: West Indian Med J 2014;63:678

Gross images

Images hosted on other servers:

Fragile grayish white mass

Microscopic (histologic) description

Per the WHO classification, based on the histologic characteristics, sinonasal adenocarcinoma is divided into
- Intestinal adenocarcinoma (ITAC)
- Nonintestinal adenocarcinoma (non-ITAC)
Non-ITAC is subsequently classified into
- Low grade
- High grade (Acta Otolaryngol 2018;138:415)
Sinonasal renal cell-like adenocarcinoma (SRCLA) is a recently described (first case in 2002) subtype of low grade non-ITAC
- SRCLA exhibits uniform, cuboidal to polyhedral glycogen rich cells with clear cytoplasm that lacks mucin production (Head Neck Pathol 2016;10:68)
ITAC displays glandular, tubular and trabecular architecture and few papillae and resembles a conventional colorectal adenocarcinoma
Exclusion of metastasis from primary gastrointestinal tract tumor is required
Low grade non-ITAC can exhibit exophytic papillae, tubular or glandular, trabecular, cribriform, clear cell and mucinous patterns
Papillae and glands are usually lined by a single layer of uniform columnar or cuboidal cells with eosinophilic cytoplasm and slight cytologic aberrations
High grade non-ITAC can display blastomatous, apocrine, mucinous, poorly differentiated patterns with pleomorphic nuclei with predominantly solid growth pattern

Microscopic (histologic) images

Contributed by Diana Bell, M.D.

Intestinal adenocarcinoma (ITAC)

Various architectures

Tubular and cribriform growth pattern

Papillary growth pattern

Nonintestinal adenocarcinoma (non-ITAC)

Low grade with uniformly located nuclei

Tubular growth pattern

Sinonasal renal cell-like adenocarcinoma

Nested architecture

Clear cytoplasm

CAIX positivity

Positive stains

Intestinal type adenocarcinoma
Nonintestinal type adenocarcinoma
- PAS positive diastase resistant intraluminal mucin
- CK7
- DOG1
- S100
- SOX10
- Focal expression of neuroendocrine markers
Sinonasal renal cell-like adenocarcinoma
- CAIX
- CD10
Reference: Head Neck Pathol 2016;10:68

Negative stains

Nonintestinal type adenocarcinoma
- CDX2
- MUC2
- CK20 (infrequently positive)
- Focal expression of neuroendocrine markers
Sinonasal renal cell-like adenocarcinoma
- PAX8
Reference: Head Neck Pathol 2016;10:68

Molecular / cytogenetics description

Intestinal type adenocarcinoma
- EGFR mutation frequently observed (Cell Oncol (Dordr) 2012;35:443)
- KRAS and BRAF mutations infrequent or absent (Oral Oncol 2012;48:692, Cell Oncol (Dordr) 2012;35:443)
- TP53 mutation in 41% of cases (J Cancer Res Clin Oncol 2021;147:1019)
- BRAF mutation in < 10% of cases
- Tumors are microsatellite stable (MSS)
- Variable beta catenin expression with aberrant nuclear expression of beta catenin in > 30% of cases
Sinonasal renal cell-like adenocarcinoma rarely shows BRAF mutation (Curr Oncol Rep 2022;24:55)

Videos

Sinonasal carcinoma: updated phenotype and molecular characterization

Malignant tumors of the paranasal sinuses by Dr. Nadir Ahmad

Sample pathology report

Ethmoidal sinus, biopsy:
- Adenocarcinoma, morphologically consistent with intestinal type adenocarcinoma

Differential diagnosis

Metastatic gastrointestinal adenocarcinoma of intestinal origin:
- Clinical history is critical and mandatory
- Histology, histochemistry and IHC of ITAC and gastrointestinal (GIT) adenocarcinoma are identical
Metastatic renal cell carcinoma:
- Must be excluded clinically and radiologically
Adenosquamous carcinoma:
- High grade neoplasm showing squamous and glandular features
Salivary gland neoplasm:
- Presence of myoepithelial cells and immunostaining positive for p53, p40, SOX10, GFAP and calponin
Seromucinous hamartomas:
- Submucosal epithelial proliferation of small glands, serous acini and tubules growing in clusters and lobules

Additional references

Curr Oncol 2021;28:2420, Int J Oral Maxillofac Surg 2017;46:422

Board review style question #1

A 66 year old man presented with a rapidly growing soft mass on his glabellar region for 4 months. He was on medication for hypertension and recently had normal endoscopy findings for gastrointestinal malignancy. The findings of the transcutaneous open biopsy are given in the image shown above. What is the most likely diagnosis?

Intestinal type adenocarcinoma
Metastatic adenocarcinoma
Mucocele
Papillary rhinosinusitis

Board review style answer #1

A. Intestinal type adenocarcinoma. Microscopy is similar to colonic adenocarcinoma but the latest screening endoscopy of the colon was normal. Answer B is incorrect because despite having a morphology similar to primary intestinal adenocarcinoma, the patient's recent gastrointestinal endoscopy was normal. Answer C is incorrect because no epithelium lined cystic mass is seen. Answer D is incorrect because there is no inflammation with polyploidal structure.

Comment Here

Reference: Nasal cavity, paranasal sinuses, nasopharynx - Adenocarcinoma-general

Board review style question #2

A 54 year old man had a soft tissue mass at the left nasal cavity and choana. A biopsy was performed and the microscopic findings are shown above. Based on the findings, the tumor of which organ should be ruled out before confirming the diagnosis?

Colon
Kidney
Lungs
Prostate

Board review style answer #2

B. Kidney. As microscopy has clear cell architecture, it is crucial to rule out clear cell renal cell carcinoma. Answer A is incorrect because clear cell colorectal carcinoma is an extremely rare entity. Answer C is incorrect because clear cell carcinoma of the lung secretes mucus, which is absent here. Answer D is incorrect because the prostate does not have presentation as well as diagnosis of prostate cancer.

Comment Here

Reference: Nasal cavity, paranasal sinuses, nasopharynx - Adenocarcinoma-general

Allergic fungal sinusitis

Table of Contents

Definition / general

Chronic allergic fungal sinusitis is an eosinophil mediated hypersensitivity reaction initiated by environmental fungi

Essential features

Characterized by thick allergic mucin (with degranulated eosinophils and Charcot crystals) and hyphal fragments on GMS stain

Terminology

Also called allergic fungal rhinosinusitis

Epidemiology

5 - 10% of all cases of chronic sinusitis (Am J Surg Pathol 1983;7:439)

Sites

Multiple; nasal cavity or paranasal sinuses

Pathophysiology

Environmental causes
A. fumigatus, A. flavus or demateaceous fungi can trigger extreme eosinophil driven hypersensitivity to fungi in susceptible individuals
Allergic fungal sinusitis is a T_H2-like lymphocyte mediated response

Clinical features

Young adult with recurrent sinonasalpolyp, asthma, poor response to medical treatment

Laboratory

Peripheral eosinophilia, elevated IgE

Radiology description

CT: opacification of the nasal cavity and one or more paranasal sinuses
Erosion of bone (skull base and orbit) is seen in 20 - 60% of cases

Case reports

24 year old woman with allergic bronchopulmonary aspergillosis with obstruction of the upper respiratory tracts (Chest 1976;70:788)
Pathologic findings in allergic aspergillus sinusitis (Am J Surg Pathol 1983;7:439)
Allergic aspergillosis of the maxillary sinuses (Thorax 1981;36:707 (abstract))

Treatment

Complete endoscopic removal of the mucus and inflamed tissue followed by intranasal or systemic corticosteroids and possible maintenance therapy with fungal desensitization vaccines

Gross description

Edematous polypoid respiratory mucosa with thick, tenacious mucus similar to peanut butter or wet clay

Gross images

Contributed by Margie Brandwein-Gensler, M.D.

Allergic fungal rhinosinusitis

Microscopic (histologic) description

Diagnostic features: eosinophilic mucin with red and blue ripples (laminations composed of cellular debris, epithelium, polymorphonuclear cells, degranulated eosinophils and Charcot Leyden crystals)
Charcot Leyden crystals are pink/red refractive, and form long needle-like structures
Rare noninvasive fungal hyphae (often found only with GMS stain)
Schneiderian mucosa reveals thickened basement membrane with goblet cell hyperplasia, and numerous inflammatory cells with prominent eosinophils
Eosinophils may have degenerative changes of smudged, elongated or basophilic nuclei

Microscopic (histologic) images

Contributed by Kelly R. Magliocca, D.D.S., M.P.H.

Eosinophilic mucin associated with allergic fungal sinusitis

Charcot-Leyden crystals

Grocott-Gomori methenamine silver

Contributed by Margie Brandwein-Gensler, M.D.

Eosinophilic mucin

Fungal detection

Differential diagnosis

It is unclear if eosinophilic mucin rhinosinusitis (EMRS) is a distinct entity from allergic fungal sinusitis (AFS) because:
Fungal hyphae are not always detected in allergic mucin, although the sensitivity for fungal detection by the gold standard Gomori methanamine silver (GMS) stain is dramatically improved by trypsin predigestion, which speaks against EMRS as a distinct entity
On the other hand, aspirin sensitivity and bilateral sinus disease are more common types of eosinophilic mucin rhinosinusitis than allergic fungal sinusitis, consistent with the idea that ERMS represents a distinct clinical entity
Thus, this issue remains unresolved

Additional references

Barnes: Surgical Pathology of the Head and Neck, Third Edition, 2008, Brandwein-Gensler: Head and Neck (Cambridge Illustrated Surgical Pathology), 2009

Allergic rhinosinusitis

Table of Contents

Definition / general

Common IgE mediated sinonasal hypersensitivity reaction provoked by reexposure to a specific antigen, including plant pollen, fungi, dust mites, animal allergens
May be acute or chronic
Also called hay fever

Terminology

Also called type I IgE immunological rhinitis
Acute allergic rhinosinusitis: develops 2 to 5 minutes after antigen-antibody exposure, reaching its peak about 15 minutes later
Chronic allergic rhinosinusitis: lasts more than 6 weeks; includes aspirin exacerbated respiratory disease

Epidemiology

10 - 20% of the U.S. adult population (Hosp Pract (Off Ed) 1991; 26:105)

Sites

Bilateral nasal cavity and paranasal sinuses

Pathophysiology

IgE antibody binding and mast cells release various mediators (histamine, prostaglandins and leukotrienes) causing vasodilation, edema, eosinophilia, nasal congenstion, rhinorrhea, sneezing and itching

Etiology

Type I IgE hypersensitive reaction to allergens, including pollen, animal dander, dust mites, mold spores and food
Aspirin exacerbated respiratory disease (AERD, also known as Samter triad) refers to the syndrome of allergic nasal polyps with eosinophils, aspirin intolerance and bronchial asthma, which affects 4 - 10% of asthmatics
AERD is due to inhibition of the cyclooxygenase pathway in sensitive individuals; this shunts metabolism of arachidonic acid to the 5-lipooxygenase pathway, leading to increased proinflammatory leukotrienes and decreased PGE2, a protective prostaglandin

Clinical features

Rhinorrhea, sneezing, itching

Laboratory

Stained smears of nasal secretion slow > 25% eosinophils
Elevated total serum IgE

Treatment

Avoidance of allergens, use of environmental controls, sublingual immunotherapy

Microscopic (histologic) description

Mucous secretions have neutrophils and prominent eosinophils

Cytology description

Stained smears of nasal secretion: > 25% eosinphils

Differential diagnosis

Infectious rhinosinusitis

Additional references

Brandwein-Gensler: Head and Neck (Cambridge Illustrated Surgical Pathology), 1st Edition, 2009, Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008

Anatomy

Table of Contents

Definition / general | Diagrams / tables

Definition / general

Nasal vestibule:

Slight dilation inside anterior aperture of nostril, lined by skin containing hair and sebaceous glands
Anterior boundary: nares
Posterior boundary: line dropped perpendicular from the frontonasal suture through the anterior aspect of the inferior turbinate
Lateral boundary: ala and lateral crus of greater alar cartilage
Medial boundary: medial crus of greater alar cartilage

Nares: anterior openings of nasal cavity

Nasal cavity:

Nasal chambers are on either side of median plane formed by nasal septum
- Anterior boundary: continuous with the vestibule
- Posterior boundary: posterior choanae
- Superior boundary: cribriform plate
- Inferior boundary: hard palate
- Medial boundary: nasal septum
- Lateral boundary: lateral nasal wall with maxillary and ethmoid ostia and turbinates
Divided into olfactory region (superior nasal turbinates and opposed septum) and respiratory region (rest of cavity)
Bulla ethmoidalis: elevation on lateral wall of middle meatus, site of opening of middle ethmoid meatus
Choanae: posterior opening of nasal cavity, communicates with nasopharynx
Columella: anterior extreme nasal septum
Crista galli: bony ridge which projects superiorly from cribriform plate
Lateral wall: contains superior, middle and inferior nasal turbinates (conchae); below each is corresponding nasal passage or meatus
Limen nasi: posterior lateral ridge separating the vestibule from the nasal cavity
Middle meatus: below and lateral to middle turbinate
Nasal septal swell body: thickened area of superior nasal septum containing nasal erectile vessels
Olfactory cleft: narrow vertical aspect of superior nasal cavity
Party wall: comprised of the lateral nasal wall and medial antral wall
Sphenoethmoidal recess: above superior turbinate, site of opening of sphenoidal sinus
Superior meatus: along upper border of middle turbinate, site of opening of posterior ethmoid meatus
Turbinates (concha):
- Scroll-like projections of bone and vascular soft tissue
- The superior turbinate is smallest, the inferior turbinate is largest
- Attaches to the lateral nasal wall anteriorly, with a free edge posteriorly

Paranasal sinuses:

Diverticula of nasal cavity that extend into neighboring bones
Frontal Sinuses:
- Most anterior, above the orbits
- Small / rudimentary at birth
- Develop through puberty
- Paired sinuses between the interior and external cranial tables
Ethmoid Complex:
- Between the orbits
- Well developed at birth
- Paired sinus complex composed of 3 to 18 cells that are grouped as anterior, middle or posterior, according to the location of their ostia
- Medial boundary: upper nasal fossa
- Lateral boundary: lamina papyracea of the orbit
- Superior boundary: fovea ethmoidalis, which is the medial extension of the orbital plate of the frontal bone
Sphenoid sinuses:
- Most posterior at base of brain
- Small / rudimentary at birth
- Develop rapidly during childhood until permanent teeth develop
- Posterior to the ethmoid sinuses
- Superior boundary: floor of the anterior cranial fossa, anteriorly
- Posterior boundary: optic chiasm and the sella turcica, posteriorly
- Lateral boundary: orbital apex, the optic canal, the optic nerve and cavernous sinus
- Inferior boundary: nasopharynx
- Anterior boundary: nasal fossa
Maxillary sinuses:
- Under the cheeks
- Small / rudimentary at birth
- Develop rapidly during childhood until permanent teeth develop
- Medial boundary: lateral wall of the nasal cavity ("party wall")
  - The curved posterolateral wall separates the sinus from the infratemporal fossa
- Anterior boundary: the facial surface of the maxilla
- Inferior boundary: hard palate
- Superior boundary: orbital rim and orbital apex
Ohngren line:
- Connects medial canthus of eye to angle of mandible
- Used to divide maxillary sinus into anteroinferior portion (infrastructure), associated with good prognosis for carcinoma and superoposterior portion (suprastructure), with a poor prognosis for carcinoma

Nasopharynx:

Respiratory passage above and behind the soft palate
Part of pharynx, which also includes oropharynx and hypopharynx
Begins anteriorly at posterior turbinates and extends along plane of airway to the level of the free border of the soft palate
Anterior wall is perforated by posterior nares (choanae)
Posterior wall is also its roof, as well as the posterior base of skull
Extends inferiorly to level of free border of soft palate where oropharynx begins
Lateral wall contains ostium of eustachian tube, surrounded by mucosa covered cartilaginous prominence
- Ostium is anterior to pharyngeal recess (fossa of Rosenmuller)

Diagrams / tables

Images hosted on other servers:

Lateral wall

Bones and cartilages

Antrochoanal polyps

Table of Contents

Definition / general | Case reports | Gross description | Microscopic (histologic) description | Microscopic (histologic) images

Definition / general

4 - 6% of nasal polyps
Frequently occur in childhood
90% solitary
Arise from wall of maxillary antrum, extending through large primary or secondary maxillary ostium into nasal cavity
May pass into choanae or nasopharynx

Case reports

27 year old woman with right nasal polyp (Case of the Week #390)

Gross description

Long narrow stalk with firm, fibrous body

Microscopic (histologic) description

Thin surface mucosa with no thickened basement membrane
Stroma with stellate cells, less edema and fewer glands than inflammatory polyp
May have prominent dilated vessels with thrombosis or infarct
Prominent eosinophils in only 20%

Microscopic (histologic) images

Case #390

Various images

Biphenotypic sinonasal sarcoma

Table of Contents

Definition / general

Low grade sarcoma of the sinonasal tract which features both neural (S100) and myogenic (actin) differentiation and the majority have been associated with PAX3 translocations

Essential features

Infiltrative, cellular, monomorphic spindled cell neoplasm with herringbone or fascicular architecture
May have prominent stromal vasculature
Positive for S100 (focal to diffuse), SMA/MSA, nuclear beta catenin immunohistochemical stains
Often recurrent PAX3 translocations most commonly partnered with MAML3

Terminology

Low grade sinonasal sarcoma with neural and myogenic features (Am J Surg Pathol 2012;36:517)

ICD coding

ICD-10: C30.0 - Malignant neoplasm of nasal cavity and middle ear

Epidemiology

M:F = 1:3
Commonly presents in the fifth decade (range: 24 - 85 years) (Virchows Arch 2018;473:615)
Rare (likely underreported)

Sites

Sinonasal tract, with the upper nasal cavity or ethmoid sinus being the most commonly involved
May extend to cribriform plate or orbit

Etiology

Unknown

Clinical features

Nonspecific, usually nasal obstructive symptoms manifesting as difficulty breathing, facial pressure, nasal congestion with or without pain

Diagnosis

CT or MRI of the nasal sinuses
Diagnosis is by endoscopic biopsy, debulking or surgical resection

Radiology description

Heterogenous, enhancing sinonasal tract polyp or mass
Could present as destructive mass with extension into orbit or anterior skull base (J Neurol Surg Rep 2017;78:e15)

Radiology images

Contributed by Josephine K. Dermawan, M.D., Ph.D. and Laura O. Rabinowitz, M.D.

Superior nasal cavity mass (coronal)

Superior nasal cavity mass (transverse)

Prognostic factors

Locally aggressive:
- Local recurrence rate 32 - 44%, majority within 5 years (Am J Surg Pathol 2019;43:747)
Rare cases of distant metastasis death from disease (~ 2%) (Virchows Arch 2018;473:615)

Case reports

35 year old woman with history of right nasal obstruction (Ann Med Surg (Lond) 2018;37:4)
39 year old woman with frontal sinus mass who died 8 months after recurrence (Hum Pathol 2016;55:44)
47 year old woman with 4.8 cm ethmoid mass (Virchows Arch 2018;473:615)
65 year old man presents with epistaxis (Ann Diagn Pathol 2018;33:6)
67 year old woman with recurrent nasal polyps (Int J Clin Exp Pathol 2017;10:11743)

Treatment

Complete surgical resection with or without radiation

Gross description

Polypoid fragments of tan-yellow to soft gray tissue

Frozen section description

Diagnostic stromal features could be subtle on frozen sections
In the presence of benign epithelial proliferation, could be mistaken for an epithelial tumor such as sinonasal papilloma or respiratory epithelial adenomatoid hamartoma on frozen section (Head Neck Pathol 2020;14:33)

Frozen section images

Contributed by Josephine K. Dermawan, M.D., Ph.D. and Laura O. Rabinowitz, M.D.

Spindled cells with invaginated nests

Cellular spindled population

Microscopic (histologic) description

Infiltrative, cellular spindled cell proliferation
Medium to long fascicles with areas of herringbone pattern
Low grade, monotonous spindled cells with ovoid to elongated nuclei and inconspicuous nucleoli
Usually absence of high grade features such as nuclear pleomorphism, frequent mitoses, significant atypia, necrosis
Invagination or entrapment of benign surface respiratory epithelial proliferation with or without squamous metaplasia
Prominent stromal thick walled vasculature, could be hemangiopericytoma-like
Delicate stromal collagen
Subset of cases show focal rhabdomyoblastic elements (variable desmin, myogenin, myoD1) (Head Neck Pathol 2020;14:33)

Microscopic (histologic) images

Contributed by Josephine K. Dermawan, M.D., Ph.D. and Laura O. Rabinowitz, M.D.

Cellular spindle proliferation

Prominent stromal vasculature

Surface epithelial invaginations

Hemangiopericytoma-like vasculature

Herringbone pattern

Medium to long fascicles

Positive S100

Positive SMA

Negative CD34

Cytology description

Bland, uniform population of spindle cells with mildly enlarged, oval to spindle shaped nuclei with fine nuclear chromatin and inconspicuous nucleoli
Significant nuclear atypia or pleomorphism is typically absent (Diagn Cytopathol 2019;47:507)

Positive stains

S100 (may be focal), smooth muscle actin (may be diffuse or focal) or calponin, muscle specific actin (patchy to diffuse), nuclear beta catenin (may be focal), desmin (variable), myogenin (variable) (Ann Diagn Pathol 2018;33:6, Hum Pathol 2016;55:44)
PAX3 (Am J Surg Pathol 2018;42:1275)

Negative stains

CD34, cytokeratins, STAT6, SOX10, synaptophysin (Hum Pathol 2016;55:44)

Molecular / cytogenetics description

Recurrent PAX3 translocations (Am J Surg Pathol 2018;42:1275)
PAX3 break apart signals on fluorescence in situ hybridization (Histopathology 2016;69:930)
Most common rearrangement: t(2;4)(q35;q31) resulting in PAX3-MAML3 fusion detected by RNA-seq or RT-PCR (Nat Genet 2014;46:666)
Other fusions reported: PAX3-NCOA1 (associated with rhabdomyoblastic differentiation), PAX3-FOXO1, PAX3-WWTR1, PAX3-NCOA2 (Am J Surg Pathol 2016;40:51, Genes Chromosomes Cancer 2016;55:25, Am J Surg Pathol 2019;43:747)

Sample pathology report

Soft tissue mass, right nasal cavity, excision:
- Biphenotypic sinonasal sarcoma (see comment and synoptic report)
- Comment: The nasal cavity mass shows a cellular spindled proliferation with areas showing a herringbone pattern. The spindle cells are low grade with slender to ovoid nuclei and inconspicuous nucleoli. There are invaginations of benign epithelium with squamous metaplasia. The neoplastic spindle cells show patchy S100, SMA and nuclear beta catenin immunohistochemical staining. They are negative for CD34, STAT6, SOX10 and cytokeratin AE1/AE3. These findings support the diagnosis of biphenotypic sinonasal sarcoma, a low-grade spindle cell sarcoma commonly associated with a PAX3-MAML3 gene fusion. This tumor type usually shows slow progressive growth and local invasion. While local recurrence is frequent, distant metastasis is very rare.

Differential diagnosis

Sinonasal glomangiopericytoma:
- Round to ovoid instead of elongated nuclei
- Diffuse smooth muscle actin and beta catenin nuclear staining positivity
- Absence of herringbone pattern
- Absence of S100 positivity
Solitary fibrous tumor:
- Ectatic, staghorn vasculature
- Thick bands of stromal collagen
- Strong and diffuse CD34 and STAT6 positivity
Schwannoma:
- Presence of hyper and hypocellular areas and nuclear palisading
- Perivascular hyalinization
- Absence of actin immunoreactivity
- Diffuse S100 and SOX10 positivity
Malignant peripheral nerve sheath tumor:
- Cellular proliferation of spindled cells arranged in herringbone-like fascicles
- Hyperchromatic and pleomorphic nuclei with readily identifiable mitoses and tumor necrosis
- Focal or weak S100 positivity
- At least focal SOX10 expression
Leiomyoma or leiomyosarcomas:
- Variably cellular proliferation of cells with blunt ended, cigar shaped nuclei
- Positive for smooth muscle actin and desmin
- Absence of S100 positivity
Spindle cell rhabdomyosarcoma:
- Affects both children and adults
- Variably number of rhabdomyoblasts
- Diffuse desmin, myogenin and MyoD1 positivity
Synovial sarcoma:
- Variable positivity for cytokeratins and TLE1
- Negative for smooth muscle actin and muscle specific actin
- Characterized by t(X;18) SS18-SSX1/2 fusions
Sinonasal papilloma, inverted type:
- Endophytic growth of markedly thickened squamous epithelial proliferation
- Absence of spindle cell proliferation
Respiratory epithelial adenomatoid hamartoma (REAH)
- Noninvasive epithelial proliferation with surface invaginations with thickened basement membrane and ciliated respiratory epithelium
- Absence of spindle cell proliferation

Additional references

Head Neck Pathol 2016;10:23

Board review style question #1

ETV6
EWSR1
NUTM1
NTRK
PAX3

Board review style answer #1

E. PAX3. Biphenotypic sinonasal sarcoma (shown here) is classically positive for S100 and actin, and is most frequently associated with PAX3 gene rearrangements, most commonly PAX3-MAML3. PAX3-NCOA1 and PAX3-FOXO1 translocations have also been reported.

Comment Here

Reference: Biphenotypic sinonasal sarcoma

Board review style question #2

Distant metastasis and death within several months of initial diagnosis
Frequent mitoses and presence of necrosis
Positive immunohistochemical reactivity for CD34
Presentation in an adolescent or young male
Uniform spindle cell proliferation with prominent stromal vasculature

Board review style answer #2

E. Uniform spindle cell proliferation with prominent stromal vasculature. Biphenotypic sinonasal sarcoma typically presents in middle aged women. Histologically, this entity is characterized by a cellular, monotonous spindle cell proliferation with low grade cytology that is positive for S100 and actin but negative for CD34 and STAT6. Prominent stromal vasculature could be present, sometimes reminiscent of hemangiopericytoma. Local recurrence is common but distant metastasis and death from disease remains rare.

Comment Here

Reference: Biphenotypic sinonasal sarcoma

Chordoma

Chronic rhinosinusitis

Table of Contents

Definition / general

Chronic inflammation of the nasal cavity (rhinitis) or the paranasal sinuses (sinusitis), symptoms lasting more than 6 weeks
Sequel to acute rhinitis (symptoms lasting 6 weeks or less), with development of secondary bacterial infection
Associated with deviated septum or nasal polyps; also ulceration and infection extending into sinuses

Essential features

Thickened, hyalinized basement membrane (minimal criteria) directly beneath respiratory epithelium and around seromucinous glandular tubuli

Terminology

Rhinosinusitis, sinusitis

Epidemiology

Most common health problem in the United States

Sites

Unilateral or bilateral, nasal cavity or paranasal sinus

Pathophysiology

Associated with deviated septum or nasal polyps
Ostial obstruction in osteomeatal compex causes anaerobic overgrowth

Etiology

Allergy, vasomotor (constricted or dilated vessels), infection, diabetes mellitus, cystic fibrosis, Kartagener syndrome, aspirin intolerance, Churg-Strauss disease, nickel exposure

Clinical features

Facial pain, pressure, congestion or fullness; nasal obstruction, blockage, discharge or purulence

Treatment

Aeration or drainage, ensuring ostial patency

Microscopic (histologic) description

Thickened basement membrane (minimal criteria) directly beneath respiratory mucosa and around seromucinous glandular tubuli
Increased lymphoplasmacytic infiltrate
Goblet cell hyperplasia and papillary hyperplasia
Squamous metaplasia can be seen and is associated with cigarette exposure

Microscopic (histologic) images

Contributed by Margie Brandwein-Gensler, M.D.

Sinonasal polyps

Chronic rhinosinusitis

Various images

Differential diagnosis

Chronic allergic sinusitis
Chronic infectious sinusitis

Additional references

Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008, Brandwein-Gensler: Head and Neck (Cambridge Illustrated Surgical Pathology), 1st Edition, 2009

Fungal ball

Table of Contents

Definition / general

Noninvasive accumulation of fungal hyphae that branch at 45 degrees
Aspergillus causes fungus balls in nasal antrum of immunocompetent patients with minimal inflammatory response, microabscesses or multinucleated giant cells
Also causes invasive aspergillosis, regardless of immune status, with extension into retroorbital region, cranium or parapharyngeal space; often fatal
Also causes allergic fungal sinusitis

Essential features

Dense fungal growth with no tissue invasion
Fruiting heads (sexual reproduction) may be seen

Terminology

Fungal ball, mycetoma, chronic noninvasive fungal sinusitis

Sites

Maxilla is most commonly affected

Pathophysiology / etiology

A. fumigatus and A. flavus are the most common isolates
Usually immunocompetent patients, often prior history of sinus disease, trauma or foreign body

Clinical features

Nasal congestion / obstruction
Sinus pain

Radiology description

Expansile massive process with bony remodeling
MR / CT signaling reflects the iron, manganese and calcium content of fungal hyphae ("iron-like signalling")

Radiology images

Images hosted on other servers:

CT of face

MR of face

Likely calcific in nature

Normal pneumatization

Opacification

Case reports

70 and 78 year old women with fungus ball of the paranasal sinuses (Int Arch Otorhinolaryngol 2012;16:286)

Treatment

Conservative curettage, irrigation with saline or iodine solution, surgery

Gross description

May present as a large, expansile mass, without involvement of the underlying mucous membrane
Grumous, friable, gray-brown-black mass, often with clotted blood

Gross images

Contributed by @Andrew_Fltv on Twitter

Fungal ball

Images hosted on other servers:

Maxillary sinusotomy

Microscopic (histologic) description

Tightly packed laminated hyphae with inflammatory exudates and cell debris
Pigmented hyphae may be dematiaceous group of fungi
Presence of characteristic fruiting heads is diagnostic for Aspergillus sp
Black conidia specifically indicate Aspergillus niger
Fungal invasion of tissue is usually not seen, although it has been reported
No / minimal host response in mucosa

Microscopic (histologic) images

Contributed by Margie Brandwein-Gensler, M.D. and @Andrew_Fltv on Twitter

Large fungus ball

Fungal hyphae, fungal sexual reproduction (fruiting heads)

Fungal ball

Aspergillus lesions of the sinuses

Images hosted on other servers:

Aspergilloma

Hyphae of mycetes

Foot

Differential diagnosis

Chronic sinusitis
Sinonasal neoplasm
Of fungal infections:
- Alternaria
- Cladosporium trichoides
- Fusarium
- Paecilomyces
- Pseudallescheria boydii
- Zygomycetes

Additional references

Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008, Brandwein-Gensler: Head and Neck (Cambridge Illustrated Surgical Pathology), 1st Edition, 2009

Glial heterotopia

Table of Contents

Definition / general

Glial heterotopia is a benign, congenital, nonneoplastic displacement of mature neuroglial tissue at extracranial sites without intracranial connection (Acta Otorhinolaryngol Ital 2022;42:317, Int J Pediatr Otorhinolaryngol 2020;129:109728, J Cutan Aesthet Surg 2020;13:233)
Very rare malformation that causes tumor-like conditions in newborns and older infants

Essential features

Most frequent in the nasal area
Mature brain tissue in the nasal cavity without connection to the dura / meninges and absence of a skull defect
Radiography is essential to rule out communication of mass with intracranial space and assess bony defects (J Cutan Aesthet Surg 2020;13:233, Medicine (Baltimore) 2018;97:e12000)

Terminology

Acceptable: ectopic glial - meningeal tissue, neuroglial heterotopia, nasal glial heterotopia, nasal glioma
Not recommended: heterotopic brain choristoma, ectopic brain tissue

ICD coding

ICD-10: Q30.8 - other congenital malformations of nose
ICD-11: LA70.Y - other specified structural developmental anomalies of the nose or cavum

Epidemiology

Incidence of congenital nasal masses is 1 in 20,000 - 40,000 live births; nasal glial heterotopia accounts for ~5% of them (Head Neck Surg 1980;2:222, Clin Otolaryngol Allied Sci 1982;7:87)
Rare association with brain or systemic anomalies
Most patients are diagnosed at birth or before the age of 3 (Int J Pediatr Otorhinolaryngol 2020;129:109728)
8% of cases are diagnosed in adults (Acta Otorhinolaryngol Ital 2022;42:317)
M:F = 3:2

Sites

Based on location related to nose, glial heterotopia can be
- Intranasal: located in the nasal cavity or sinuses
- Extranasal: protruding from the nasal root within the subcutaneous tissue of the nose
- Mixed type: present in both locations (Int J Pediatr Otorhinolaryngol 2020;129:109728)
Bridge of nose is the most commonly involved site (Int J Pediatr Otorhinolaryngol 2020;129:109728)
Rare occurrence at other sites, including orbit, lung, uterine cervix, endometrium, lip, tongue, pharynx, tonsil, palate and maxilla (Ophthalmic Plast Reconstr Surg 2020;36:2, J Cutan Aesthet Surg 2020;13:233, Ophthalmic Plast Reconstr Surg 2015;31:e26, Arch Ophthalmol 2003;121:119)

Pathophysiology

Congenital, nonhereditary malformation
Development of nasal cerebral heterotopia is embryologically similar to that of nasal encephalocele or dermoid
During retraction of the embryonic dural diverticulum, remnants of neural glial tissue become sequestered when their connections to the subarachnoid space are pinched off and obliterated
Lack of subarachnoid communication distinguishes heterotopia from anterior encephalocele
Distinction between glioma and encephalocele is not possible based on histopathologic findings because glial tissue may be the predominant or exclusive component in both types of lesions (Acta Otorhinolaryngol Ital 2022;42:317)

Etiology

See Pathophysiology

Clinical features

Intranasal: nasal congestion, mass, obstruction or deformity, may be asymptomatic (Ann Diagn Pathol 2003;7:354)
Extranasal: firm, smooth masses that do not pulsate or expand during crying, coughing or straining (Acta Otorhinolaryngol Ital 2009;29:218)

Diagnosis

Diagnosis requires strong clinical and radiologic correlation in addition to histology of lesion
Magnetic resonance imaging (MRI) to exclude communication with the central nervous system and plan a surgical approach
Additional computed tomography (CT) performed if bony involvement is suspected or necessary for endoscopic surgery (Acta Otorhinolaryngol Ital 2022;42:317)

Radiology description

Radiology is necessary to determine the location of the mass and its relationship to the skull base
MRI characteristics of glial heterotopia resemble normal brain tissue in all pulse sequences
Cystic elements might be present and represent cerebrospinal fluid (CSF)-like fluid filled spaces
MRI findings (J Cutan Aesthet Surg 2020;13:233, Acta Otorhinolaryngol Ital 2022;42:317)
- Circumscribed, ovoid soft tissue intensity lesion
- Isointense signal in T1 weighted imaging
- Heterogeneously hyperintense signal in T2 weighted imaging
- Moderate enhancement postintravenous gadolinium contrast
- No connection between the mass and the dura or brain
Noncontrast computed tomography (NCCT): soft tissue density, space occupying lesion with no communication with nasal cavity or brain (J Cutan Aesthet Surg 2020;13:233)

Radiology images

Contributed by Nasir Ud Din, M.B.B.S.

Nasal swelling

Nasal cavity lesion

Nasal cavity mass

Prognostic factors

Benign lesion with good prognosis (Int J Pediatr Otorhinolaryngol 2020;129:109728)
Local recurrence rate: up to 30% with incomplete excision
Histological evaluation of surgical margins can reduce the risk of recurrence
Most recurrences occur within the first 12 months

Case reports

2 month old boy presented with nasal obstruction and shortness of breath since birth (Medicine (Baltimore) 2020;99:e21200)
6 month old infant with a congenital mass located at the root of the nose (J Cutan Aesthet Surg 2020;13:233)
16 year old girl presented with sore throat and feeling of lump in her throat (BJR Case Rep 2020;6:20190116)
37 year old man presented with right nasal obstruction, epistaxis and headache (Head Neck 2008;30:549)

Treatment

Complete surgical resection is the curative treatment (Int J Pediatr Otorhinolaryngol 2020;129:109728, J Cutan Aesthet Surg 2020;13:233)
Surgical approach depends on the location and extent of lesion: external rhinotomy, endoscopic resection or combined approach are the most common techniques

Clinical images

Images hosted on other servers:

External nasal lesion with skin tightening

Globular swelling at the root of nose

Nasal endoscopy

Gross description

Size range: 1 - 3 cm; can grow up to 7 cm
Firm, globular to polypoidal smooth mass with homogenous gray to pearly white cut surface (J Cutan Aesthet Surg 2020;13:233)
Grows slowly in proportion to adjacent tissue

Gross images

Images hosted on other servers:

Homogeneous, tan, firm cut surface

Microscopic (histologic) description

Nonencapsulated lesion with ill defined edges
Composed of variable sized mats and nests of benign and mature brain tissue in a background of vascularized connective tissue
Histologically, brain tissue shows a predominant glial component and minimal neuronal component if present
Glial component shows evenly dispersed astrocytes in a fine, neurofibrillary matrix
Interspersed large gemistocytes, ependyma, choroid plexus, retinal epithelium, cerebellar tissue and leptomeninges may be present (J Cutan Aesthet Surg 2020;13:233)
Rare proliferation of eccrine ducts
Longstanding lesions show fibrosis and collagen
Large amount of fibrotic tissue can undermine the glial tissue in H&E sections
Inflammation, focal calcification may be seen
Mitoses are absent

Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.

Polypoid lesion

Syncytial architecture

Nested architecture

Astrocytes in fibrillary matrix

Astrocyte morphology

Astrocytes in mild inflammatory stroma

Vascularized background

Fibrotic appearance

Positive GFAP expression

Positive stains

GFAP (cytoplasmic) (Br J Ophthalmol 1993;77:817)
S100
Neurofilament: stains axons
NeuN: stains neurons
SSTR2A: highlights leptomeninges and arachnoid cells (Childs Nerv Syst 2022;38:63)
Special stain Masson trichrome shows red staining of the glial tissue, whereas the background fibrosis appears blue (J Cutan Aesthet Surg 2020;13:233)

Negative stains

Molecular / cytogenetics description

Not required for routine diagnosis
Copy number profiling from global DNA methylation data showed a balanced genome
One case showed significant copy number variation involving loss of chromosomes 16, 17 and 19 and gain of chromosomes 4 and 5 (Childs Nerv Syst 2022;38:63)

Sample pathology report

Nasal swelling, excision:
- Glial heterotopia, intranasal type (see comment)
- Resection margin is free
- Comment: The tissue shows respiratory epithelium covered unencapsulated polypoid lesion with poorly defined borders. The lesion is composed of nests and patches of mature glial tissue showing evenly dispersed astrocytes in a fine, neurofibrillary matrix. Mitosis is absent. Based on combined radiologic features and histologic findings, the lesion is best characterized as nasal glial heterotopia. This lesion is typically benign with recurrence associated with incomplete excision.

Differential diagnosis

True encephalocele:
- Extracranial hernias of the meninges or brain caused by congenital defects in the skull
- Intracranial connection present (Medicine (Baltimore) 2018;97:e12000)
- Histologically similar to heterotopia; imaging required for correlation
- Due to shared molecular alterations in a subset of nasal glial heterotopia and encephalocele, there is a strong suggestion that these 2 entities represent the same histopathologic entity (Childs Nerv Syst 2022;38:63)
Teratoma:
- Congenital or developmental tumor derived from multipotent cells
- Extremely rare (2%) in head and neck region (Int J Pediatr Otorhinolaryngol 2015;79:1991)
- May present as a congenital nasal midline mass
- Differentiate into diverse types of tissue derived from the 3 germ layers (Chest 2005;128:2893)
- Histology shows derivatives of germ layers in variable combination
- Mature type contains neural tissue, teeth, skin, hair, fat, bone, cartilage, respiratory or intestinal epithelium
- Immature type has additional primitive neuroepithelium with rosettes, pseudorosettes or neurofibrillary matrix in some tumors (Iran J Otorhinolaryngol 2018;30:355)
Neurofibroma:
- Neural tumor occurs in second or third decades of life
- Wide anatomic distribution but diffuse type neurofibromas usually arise in the head and neck region
- Histology shows spindle cells with wavy, tapering nuclei arranged haphazardly or in fascicles
- Stroma shows collagenous (shredded carrot collagen or homogeneous pink) rather than fibrillary appearance
- CD34 positive
Ectopic meningioma / meningothelial hamartoma:
- Meningothelial neoplasm arises in children and young adults
- Usually occurs in the head and neck
- Histology shows syncytial lobules and whorls of spindle cells with regular nuclei and pale intranuclear cytoplasmic inclusions
- May show psammomatous calcifications
- Meningothelial hamartoma arises in infants; most common site is posterior scalp
- Shows slit-like pseudovascular spaces lined by spindle cells along with small clusters in a fibrocollagenous stroma
- EMA positive
Congenital hemangioma:
- Benign vascular tumor, fully developed at birth (BMJ Paediatr Open 2020;4:e000816)
- Superficial, occurs commonly in head and neck region
- Have similar clinical presentations as heterotopia
- Usually presents as a reddish purple limited lesion covered with fine or coarse telangiectasia
- Frequently shows a pale peripheral halo (BMJ Paediatr Open 2020;4:e000816)
- Prenatal ultrasound diagnosis between nasal glial heterotopia and congenital hemangioma is difficult
- Fetal MRI is not very specific for distinguishing between the 2 lesions but excludes the presence of an intracerebral connection in case of heterotopia
- Postnatal exams are more specific (J Stomatol Oral Maxillofac Surg 2017;118:298)
- Histology shows poorly canalized vessels and mitotically active endothelium in rapid growth phase
- Lumina become prominent with maturation and a combination of solid and vascular areas in varying proportions may be seen
Ganglioglioma:
- Glioneuronal tumor that makes up ~2% of all primary intracranial tumors (Childs Nerv Syst 2016;32:1839)
- Predilection for children and young adults (median age: 12 years)
- Mostly occurs in temporal lobe
- Histology shows biphasic tumor with variable mixture of mature appearing ganglion-like cells and atypical glial cells
- Large ganglion-like cells may show bi or multinucleation
- Atypical glial cells show moderate enlargement with hyperchromasia and mimic those of fibrillary astrocytomas, pilocytic astrocytoma or oligodendroglioma
- May show perivascular lymphocytic cuffing, eosinophilic granular bodies and dystrophic calcifications (Childs Nerv Syst 2022;38:63)

Additional references

Diagnostics (Basel) 2023;13:2796, Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021;56:117, Pediatr Investig 2021;5:69

Board review style question #1

A 6 month old infant presented with swelling in the nose since birth. Radiology showed a well circumscribed lesion with no connection to brain or dura. Histological examination revealed nests of glial tissue embedded in a fibrillary stroma. Which immunostain will be most likely expressed by the lesional cells?

CD34
Desmin
EMA
GFAP
SMA

Board review style answer #1

D. GFAP. The glial tissue will be immunopositive for GFAP (J Cutan Aesthet Surg 2020;13:233, Br J Ophthalmol 1993;77:817). Answer A is incorrect because CD34 is a vascular marker and also shows positive expression in some fibrohistiocytic lesions. Answer B is incorrect because desmin is a myogenic marker expressed in skeletal muscle and smooth muscle lesions. Answer C is incorrect because EMA is positive in meningeal and epithelial cells (Oncol Lett 2013;5:768, J Oral Maxillofac Pathol 2023;27:604). Answer E is incorrect because SMA is expressed in smooth muscle cells and myofibroblasts in normal, reactive or neoplastic tissue.

Comment Here

Reference: Glial heterotopia

Board review style question #2

A 2 year old child underwent surgical resection of a nasal mass. The histology was consistent with nasal glial heterotopia. What is the possible behavior of this lesion?

Benign
Intermediate, locally aggressive
Intermediate, rarely metastasizing
Malignant
Uncertain potential

Board review style answer #2

A. Benign. Nasal glial heterotopia is a benign lesion with a very good prognosis. Recurrence rate is low and related to incomplete excision (Int J Pediatr Otorhinolaryngol 2020;129:109728). Answers B - E are incorrect because the lesion does not show intermediate or malignant features.

Comment Here

Reference: Glial heterotopia

Grossing & features to report

Table of Contents

Grossing | Features to report

Grossing

Grossing of the sinonasal tract is extremely complicated, as the extent of each surgery (composite resection) varies. Therefore, the sampling of each specimen is unique, and consultation with the surgeon and an experienced head and neck pathologist is recommended.

At least one section per 1 cm of tumor for large tumors, including tumor center and periphery
Submit entire tumor, if possible in < 5 sections
Submit resection margins
Submit samples of tissue from other sites

Features to report

Tumor histologic type and pattern
Tumor size and location
Tumor histologic grade
Tumor extension to adjacent structures
Status of resection margins
Vascular invasion
Perineural invasion
Lymph nodes: for each level, number obtained, number involved by tumor, size of nodal metastases, presence of extracapsular spread

Features to report by organization:

Hairy polyp

Table of Contents

Definition / general

Benign nasopharyngeal lesion
Polypoid lesion containing both ectodermal and mesodermal components

Essential features

Polypoidal lesions are often pedunculated with bigerminal origin
Congenital, usually presents in newborns
Comprised of only ectoderm and mesodermal cell lines; no endoderm
Skin covered polypoid mass with mesoderm core

Terminology

Not recommended: dermoid polyp, teratoid polyp, naso-oropharyngeal choristoma

ICD coding

ICD-11: 2E90.6 - benign neoplasm of nasopharynx

Epidemiology

Rare (1/40,000 live births) (Am J Case Rep 2021;22:e930200)
Usually presents in neonates and young children
F > M

Sites

Lateral wall of nasopharynx (most common) (Medicine (Baltimore) 2019;98:e14305)
Oropharynx, lip, tongue, palate, tonsillar areas and middle ear (Head Neck Pathol 2013;7:232)

Pathophysiology

Pathogenesis is unclear
May be branchial arch anomaly or misdirected totipotent cells (Medicine (Baltimore) 2019;98:e14305)
Closure failure of naso-oropharyngeal plates during organogenesis (Head Neck Pathol 2013;7:232)

Etiology

Unknown

Diagrams / tables

Images hosted on other servers:

Epidemiology and clinical features over 2 decades

Clinical features

Varies based on extent, site and mobility of the lesion
Spectrum ranges from asymptomatic to lethal presentation
Presents as polyhydramnios prenatally in 20 - 30% of cases (Ear Nose Throat J 2022;101:NP68)
Most common symptom is respiratory obstruction (Am J Case Rep 2021;22:e930200)
Others include snoring, feeding difficulties, cyanosis, cough, stridor, dyspnea, vomiting and recurrent middle ear infections (BMJ Case Rep 2015;2015:bcr2015209825)
Smaller polyps and polyps in nasopharynx and middle ear remain silent until adulthood
Rare associations: branchial arch anomalies, cleft palate, choanal atresia or Dandy-Walker syndrome (Int J Clin Pediatr Dent 2009;2:46, J Med Genet 1990;27:788)
Autoamputation occurs infrequently (Radiol Case Rep 2021;16:1570)
Can be occasionally bilateral (Braz J Otorhinolaryngol 2017;83:117)

Diagnosis

Ear, nose and throat (ENT) examination (Ear Nose Throat J 2022;101:NP68)
Flexible endoscopy (Am J Respir Crit Care Med 2019;200:924)
CT or MRI to assess the extent of lesion and to exclude intracranial extension (Ear Nose Throat J 2022;101:NP105, BMJ Case Rep 2015;2015:bcr2015209825)
Histopathological examination is confirmatory (Am J Case Rep 2021;22:e930200)

Laboratory

No specific laboratory findings

Radiology description

CT findings: sausage shaped mass with fat attenuation (Diagnostics (Basel) 2023;13:1328)
MRI: multilayered mass with hyperintense signal on both T1 and T2 with a linear internal low signal (Eurorad: Nasopharyngeal Hairy Polyp in an Infant with Apnoiec Spells [Accessed 6 September 2023])
Contrast: variable stalk enhancement with no lesion enhancement on both CT and MRI

Radiology images

Contributed by Muthu Kumar Sakthivel, M.D.

Mass with fat attenuation

Pedunculated tubular fatty mass

3 dimensional reconstructed oral lesion

Images hosted on other servers:

Nasal oropharyngeal mass

Nasal vestibule mass

Prognostic factors

Excellent prognosis
No recurrence or malignancy reported (Case Rep Otolaryngol 2013;2013:374681)
Rarely may be life threatening due to bleeding, choking or autoamputation (Int J Otolaryngol 2022;11:75)

Case reports

Newborn girl with severe respiratory distress due to hairy polyp of eustachian tube (Congenit Anom (Kyoto) 2015;55:158)
Newborn boy with nasopharyngeal hairy polyp arising from eustachian tube (Head Neck Pathol 2016;10:213)
Full term newborn boy with intermittent dyspnea and cyanosis due to hairy polyp (Pediatr Neonatol 2014;55:231)
2 day old preterm infant girl with oral mass (Case Rep Otolaryngol 2013;2013:374681)
15 month old boy with rare occurrence of 2 separate hairy polyps with meningothelial components (Case Rep Otolaryngol 2021;2021:1844244)
3 year old boy with respiratory distress due to nasopharyngeal hairy polyp from supratonsillar region (Int Arch Otorhinolaryngol 2015;19:90)

Treatment

Surgical excision is curative (Head Neck Pathol 2016;10:213)

Clinical images

Contributed by Ezer Benaim, M.D.

Mobile oropharyngeal mass

Nasal endoscopy

Images hosted on other servers:

Polypoid lesion from mouth

Gross description

Grossly, skin covered polypoid and pedunculated / sessile lesion (Medicine (Baltimore) 2019;98:e14305)
Hair growth on the external surface (Medicine (Baltimore) 2019;98:e14305)
Cut surface: tan-yellow and mostly solid

Gross images

Images hosted on other servers:

Skin covered pedunculated lesion

Polypoidal lesion

Microscopic (histologic) description

Comprised of tissue derived from ectoderm and mesoderm
Consists of keratinizing squamous epithelium with underlying adnexa which includes pilosebaceous units
Mesoderm derivatives include fibroadipose tissue, skeletal muscle, smooth muscle, seromucous glands and cartilage
Meningothelial cells have been reported in literature occasionally (Case Rep Otolaryngol 2021;2021:1844244, Head Neck Pathol 2021;15:25)
No endodermal elements are present

Microscopic (histologic) images

Contributed by Surekha Bantumilli, M.D. and Steven Johnson, M.D.

Squamous epithelium

Polypoidal appearance

Stratified squamous epithelium

Mesoderm derivative

Mesenchymal core

Sample pathology report

Right oral cavity lesion, excision:
- Hairy polyp (see comment)
- Comment: Squamous epithelium with underlying adnexal structures, cartilage and fibroadipose tissue are present.

Differential diagnosis

Teratoma (Turk Arch Otorhinolaryngol 2015;53:188):
- Comprised of 3 germ layers
- Solid or cystic with mature and immature components
Hamartoma:
- Disordered growth of cells or tissue in normal anatomical location
Dermoid cyst (Ear Nose Throat J 2022;101:NP105):
- Consists of squamous epithelium with adnexal structures
- No other derivatives present
Choristoma (Turk J Pediatr 2018;60:460, Eurorad: Nasopharyngeal Hairy Polyp in an Infant with Apnoiec Spells [Accessed 6 September 2023]):
- Histologically normal tissue in abnormal anatomical location

Additional references

Rambam Maimonides Med J 2022;13:e0006

Board review style question #1

A 2 day old neonate presents with airway obstruction and oropharyngeal mass since birth. There are no underlying congenital deformities. Flexible endoscopy demonstrates a mass extending from the left torus tubarius into the oral cavity which is excised for histopathological examination. Microscopic examination displays epidermal squamous epithelium with underlying pilosebaceous units and mesenchymal core (depicted in the image above). What is the diagnosis?

Dermoid cyst
Hairy polyp
Squamous papilloma
Teratoma

Board review style answer #1

B. Hairy polyp. Hairy polyp is comprised of 2 germ layers, which are ectoderm and mesoderm derivatives. Answer D is incorrect because teratoma contains derivative from all 3 layers. Answer C is incorrect because squamous papillomas show finger-like projections with squamous epithelium and fibrovascular cores. Answer A is incorrect because it is a midline cyst with squamous epithelium and adnexal structures only.

Comment Here

Reference: Hairy polyp

Board review style question #2

A neonate presents with a finger-like polypoidal extension of soft tissue mass from oral cavity (depicted in the clinical picture above) with feeding difficulties and airway obstruction requiring intubation. The baby has had this lesion since birth. The microscopic examination shows keratinizing squamous epithelium with adnexal structures, adipose tissue, skeletal muscle and cartilaginous core. What is the most likely diagnosis in this case?

Hairy polyp
Hamartoma
Lipoma
Teratoma

Board review style answer #2

A. Hairy polyp. Hairy polyps occur congenitally and are comprised of mesodermal core with ectodermal lining. Answer C is incorrect because lipomas contain mature adipose tissue. Answer D is incorrect because teratomas contain derivatives from all 3 germ layers. Answer B is incorrect because hamartomas have a haphazard growth of cells in a normal anatomical location.

Comment Here

Reference: Hairy polyp

High grade neuroendocrine carcinoma

Table of Contents

Definition / general

High grade / poorly differentiated neuroendocrine carcinoma, characterized by high mitotic count and (comedo type) tumor necrosis, morphologically similar to high grade neuroendocrine carcinoma occurring in other body sites

Essential features

Diagnosis dependent on histologic and immunohistochemical evidence of neuroendocrine differentiation
Can be further classified as small cell (neuroendocrine) carcinoma and large cell neuroendocrine carcinoma
May be combined with another type of nonneuroendocrine carcinoma, most frequently squamous cell carcinoma, termed as combined carcinoma

Terminology

Poorly differentiated neuroendocrine carcinoma
Small cell carcinoma
Small cell neuroendocrine carcinoma
Large cell neuroendocrine carcinoma
Neuroendocrine carcinoma, large cell type

ICD coding

ICD-O
- 8013/3 - large cell neuroendocrine carcinoma
- 8041/3 - small cell carcinoma, NOS
- 8045/3 - combined small cell carcinoma

Epidemiology

Sinonasal small cell carcinoma accounts for ~35% of all head and neck small cell carcinomas (Laryngoscope 2017;127:1785)
Mean age of presentation is in the 50s (Oral Oncol 2016;63:1, Int Forum Allergy Rhinol 2016;6:744, Laryngoscope 2017;127:1785)

Sites

Nasal cavity, including nasal septum, is the most common site, being involved in 32 - 45% of cases (Int Forum Allergy Rhinol 2016;6:744, Laryngoscope 2017;127:1785)
Other sites in descending order include maxillary sinus, ethmoid sinus, frontal sinus and sphenoid sinus

Etiology

Subset is associated with high risk human papillomavirus (HPV) (Am J Surg Pathol 2013;37:185, Virchows Arch 2015;467:405)

Clinical features

Nasal congestion and obstruction and epistaxis are the most common presenting symptoms, followed by facial pain, palpable facial mass and exophthalmos (Int Forum Allergy Rhinol 2016;6:744)

Diagnosis

Diagnosis relies on demonstration of neuroendocrine differentiation, histologic features of small cell or large cell neuroendocrine carcinoma, high mitotic index (> 10 per 2 mm²) and tumor necrosis

Radiology description

Destructive soft tissue mass of the sinonasal tract

Radiology images

Images hosted on other servers:

Mass of maxillary sinus

Prognostic factors

Diagnosis designates a poor prognosis: 5 year disease specific survival of sinonasal small cell carcinoma is 46% (Oral Oncol 2016;63:1)
Frequent local recurrence and distant metastasis despite multimodal therapy
Stage does not appear to affect the prognosis (Oral Oncol 2016;63:1)

Case reports

22 year old woman with small cell carcinoma of the maxillary sinus (Natl J Maxillofac Surg 2013;4:111)
50 year old woman with HPV associated combined neuroendocrine carcinoma and squamous cell carcinoma in the nasal cavity (Head Neck Pathol 2022;16:1227)
56 year old woman with large cell neuroendocrine carcinoma of the nasal cavity (NMC Case Rep J 2021;8:485)
68 year old man with small cell carcinoma of the paranasal sinus with intraoral extension (J Oral Maxillofac Pathol 2017;21:286)

Treatment

There are no specific management guidelines due to rarity of the tumor
Multimodality treatment has been used with variable results
- Most common treatment modality is combined chemotherapy and radiation therapy (Int Forum Allergy Rhinol 2016;6:744)

Clinical images

Images hosted on other servers:

Expansile swelling of maxilla

Microscopic (histologic) description

High grade neuroendocrine carcinoma (general features)
- Mitotic index > 10 mitoses per 2 mm², frequent apoptotic bodies and tumor necrosis
- Solid sheets or trabeculae of tumor cells, sometimes with peripheral palisading or rosette formation
Small cell carcinoma
- Small to medium sized cells: the diameter of tumor cells is < 3 times the diameter of a lymphocyte
- Scanty cytoplasm and indistinct cell boundary
- Finely granular salt and pepper chromatin
- No or inconspicuous nuclei
- Nuclear molding (conformity of adjacent nuclei to one another), nuclear spindling and crush artifacts of the nuclei may be seen
Large cell neuroendocrine carcinoma
- Large sized cells: the diameter of tumor cells is > 3 times the diameter of a lymphocyte
- Abundant amphophilic to eosinophilic cytoplasm and distinct cell membrane
- Large nuclei with prominent nucleoli; chromatin pattern is variable, ranging from granular, vesicular, to coarse
Combined neuroendocrine carcinoma
- Tumor that is composed of a high grade neuroendocrine carcinoma and a nonneuroendocrine carcinoma, commonly a squamous cell carcinoma

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Small cell carcinoma

Finely granular chromatin

Frequent mitoses and nuclear molding

CAM5.2 (dot-like pattern)

Synaptophysin

Chromogranin

INSM1

Elevated Ki67 proliferation index

TTF1

Large cell neuroendocrine carcinoma

Large tumor cells

Synaptophysin

Chromogranin

Combined small cell carcinoma and squamous cell carcinoma

Squamous and neuroendocrine component

p40

Cytology description

Small cell carcinoma: hypercellular sample, individual cells or small loose clusters, hyperchromatic nuclei, no nucleoli, nuclear molding, crush artifact and necrotic background

Cytology images

Contributed by Bin Xu, M.D., Ph.D.

Small cell carcinoma

Positive stains

Neuroendocrine markers such as chromogranin, synaptophysin and INSM1
Cytokeratin AE1 / AE3 and CAM5.2: often show perinuclear dot-like staining pattern
EMA
TTF1 can be positive in high grade neuroendocrine carcinoma of sinonasal tract (Hum Pathol 2002;33:642)
Ki67 proliferation index: by definition > 20% but is often much higher (> 50%)

Negative stains

NUT
No loss of SWF / SNF pathway proteins: immunoexpression of INI1 / SMARCB1 or SMARCA4 / BRG1 is retained
S100

Molecular / cytogenetics description

Subset of large cell neuroendocrine carcinoma has IDH2 R172 mutation (Mod Pathol 2019;32:1447)
Small cell carcinoma does not have IDH2 mutation but may harbor ARID1A mutation (Mod Pathol 2019;32:1447)

Sample pathology report

Nasal cavity, biopsy:
- Small cell carcinoma (high grade neuroendocrine carcinoma, small cell carcinoma type) (see comment)
- Comment: Immunohistochemistry studies show that the tumor is diffusely positive for synaptophysin, chromogranin, INSM1, cytokeratin AE1 / AE3 and CAM5.2, whereas it is negative for S100 and NUT. Immunoexpression of SMARCA2, SMARCA4 and SMARCB1 is retained in this tumor. Ki67 proliferation index is > 90%. The overall histologic features and immunoprofile support the diagnosis.

Differential diagnosis

Olfactory neuroblastoma:
- Both entities are positive for synaptophysin and chromogranin
- Olfactory neuroblastoma usually has S100 positive sustentacular network and is negative for keratins (such as cytokeratin AE1 / AE3 and CAM5.2) and EMA
- Low grade olfactory neuroblastoma lacks necrosis and has a low mitotic index
NUT carcinoma:
- Synaptophysin and chromogranin positivity can be seen in NUT carcinoma (Hum Pathol 2022;126:87)
- NUT immunopositivity or detection of NUTM1 translocation is essential for the diagnosis
SWI / SNF complex deficient sinonasal carcinoma:
- 52% of SMARCB1 deficient sinonasal carcinomas express synaptophysin or chromogranin (Hum Pathol 2020;104:105)
- Loss of immunoexpression of SMARCB1, SMARCA2 or SMARCA4 is required for the diagnosis
Sinonasal undifferentiated carcinoma (SNUC):
- SNUC can show very focal synaptophysin and chromogranin positivity (Am J Surg Pathol 2001;25:156)
- More than focal or diffuse synaptophysin and chromogranin immunopositivity excludes a diagnosis of SNUC

Additional references

WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2022

Board review style question #1

A biopsy was performed from a nasal cavity mass of a 60 year old man. The H&E, CAM5.2 and synaptophysin immunohistochemistry slides are shown above. What is the diagnosis?

Large cell neuroendocrine carcinoma
Olfactory neuroblastoma
Sinonasal undifferentiated carcinoma
Small cell carcinoma

Board review style answer #1

D. Small cell carcinoma. The tumor shows diffuse synaptophysin expression and perinuclear dot-like expression of CAM5.2. The tumor cells have scanty cytoplasm, salt and pepper chromatin, inconspicuous nuclei, frequent mitoses and apoptotic bodies. Answer C is incorrect because diffuse synaptophysin expression excludes a diagnosis of sinonasal undifferentiated carcinoma. Answer B is incorrect because olfactory neuroblastoma is cytokeratin negative, while this tumor expresses CAM5.2. Answer A is incorrect because the tumor cells lack abundant cytoplasm and prominent nucleoli.

Comment Here

Reference: High grade neuroendocrine carcinoma

Board review style question #2

Which of the following statements is true for high grade neuroendocrine carcinoma of the sinonasal tract?

It is generally positive for INSM1 and S100
It is universally negative for high risk human papillomavirus (HPV), distinguishing it from HPV related squamous cell carcinoma and HPV related multiphenotypic sinonasal carcinoma
It may coexist with a squamous cell carcinoma
Ki67 proliferation index is between 2% and 20%

Board review style answer #2

C. It may coexist with a squamous cell carcinoma. High grade neuroendocrine carcinoma may coexist with a nonneuroendocrine carcinoma component (i.e., combined carcinoma). Answer B is incorrect because a subset can be positive for high risk human papillomavirus. Answer D is incorrect because Ki67 by definition should be > 20%. Answer A is incorrect because it is generally negative for S100.

Comment Here

Reference: High grade neuroendocrine carcinoma

Histology

Table of Contents

Definition / general

Nasal cavity

Lined by stratified squamous and respiratory type pseudostratified columnar epithelium, separated by transitional epithelium in some places
Respiratory mucosa (also called Schneiderian membrane) may contain goblet cells; may undergo squamous metaplasia
Superior third of nasal septum, superior turbinate and cribriform plate are covered with thinner olfactory mucosa, usually patchy in adults, which has neuroendocrine features
Seromucinous glands (resembling salivary glands) are present in submucosa, numerous near eustachian tube opening of nasopharynx, may undergo oncocytic metaplasia with increasing age
Normally no lymphoid tissue

Nasopharynx

Lined by stratified squamous epithelium (inferior anterior and posterior walls and anterior lateral walls) and respiratory type epithelium (around nasal choanae and roof of posterior wall); remaining areas have mixtures of squamous and respiratory or intermediate epithelium (also called transitional although it does not resemble urothelium ultrastructurally)
Intermediate epithelium is usually concentrated as a wavy ring at junction of nasopharynx and oropharynx
Seromucinous glands may undergo oncocytic metaplasia and rarely form a mass or obstruct eustachian tube
Abundant lymphoid tissue present, particularly at rim of eustachian tube opening (Gerlach tonsil); functionally equivalent to that of GI tract or mucosal associated lymphoid tissue (MALT)

Paranasal sinuses

Mucosa is continuous with nasal cavity and identical (respiratory type epithelium) but thinner and with fewer goblet cells and seromucinous glands
Normally no lymphoid tissue

HPV related multiphenotypic sinonasal carcinoma

Table of Contents

Definition / general

Unique type of carcinoma characterized by its association with high risk human papillomavirus (HPV, in particular type 33), exclusive sinonasal location and mixed histologic phenotype (resembling both adenoid cystic carcinoma and squamous cell carcinoma)

Essential features

Located exclusively within the sinonasal tract
Positive for HPV, in particular type 33 and negative for MYB / MYBL1 / NFIB translocation
Exhibits various histologic features, including areas that resemble adenoid cystic carcinoma, squamous cell carcinoma, carcinoma with basaloid appearance

Terminology

HPV related sinonasal carcinoma with adenoid cystic carcinoma-like features

ICD coding

Newly described in 2013 and does not have its own ICD code (Am J Surg Pathol 2013;37:185)
Included in the current WHO classification as a provisional entity under sinonasal nonkeratinizing squamous cell carcinoma
- ICD-0: 8072/3 - squamous cell carcinoma, large cell, nonkeratinizing, NOS

Epidemiology

Age of initial presentation: from 28 - 90 (mean age: 54)
M:F = 1:1.6 (Am J Surg Pathol 2017;41:1690)

Sites

Occurs exclusively in the sinonasal tract (Am J Surg Pathol 2017;41:1690)
Approximately 57% affects nasal cavity, 10% paranasal sinus and the rest affects both sites
Involvement of adjacent sites, e.g. lacrimal duct, cranial fossa and orbit, is rare but has been reported (Arch Pathol Lab Med 2019 Mar 6 [Epub ahead of print])

Etiology

High risk HPV is detected in all reported cases (Am J Surg Pathol 2017;41:1690)
HPV type 33 detected in 68% of cases; other uncommon HPV types are 35 (6% of cases), 56, 16, 52 and 26 (Head Neck Pathol 2018 Sep 26 [Epub ahead of print])

Clinical features

Usually present with nonspecific symptoms, e.g. nasal congestion, discharge, nasal obstruction, epistaxis and pain

Radiology description

Locally destructive mass involving nasal cavity or paranasal sinus (AJNR Am J Neuroradiol 2019;40:584)

Radiology images

Images hosted on other servers:

Aggressive mass in the inferior nasal cavity

Prognostic factors

No known prognostic factor
Overall appears to be more indolent than sinonasal squamous cell carcinoma
Based on the reported cases
- Associated with high frequency (36%) of local recurrence, including late local recurrence decades after the initial surgery (J Pathol Transl Med 2019 Apr 25 [Epub ahead of print], Head Neck Pathol 2018;12:623)
- Distant metastases are rare, occurring in 5% of patients 8 - 17 years after the initial resection
- No reported case with regional lymph node metastasis (Am J Surg Pathol 2017;41:1690)

Case reports

36 year old woman with nasal cavity mass that recurred 33 years after the initial resection (Head Neck Pathol 2018;12:623)
48 year old woman with epistasis and a nasal cavity mass (Head Neck Pathol 2018 Sep 26 [Epub ahead of print])
66 year old man with a polypoid lesion in the right nasal cavity (J Pathol Transl Med 2019 Apr 25 [Epub ahead of print])

Treatment

Knowledge on the appropriate treatment for this rare tumor is limited; based on the reported cases (Am J Surg Pathol 2017;41:1690):
- Surgical resection with appropriate margin is the main treatment approach
- Approximately 40% of patients also receive adjuvant radiation therapy
- Given the reported negligible risk of regional lymph node metastasis and low risk of distant metastasis, routine regional lymph node dissection or chemotherapy may not be indicated
- Late local recurrence and distant metastasis may occur, therefore long term clinical follow up may be warranted

Microscopic (histologic) description

Typical microscopic features include:
- Areas resemble adenoid cystic carcinoma of salivary gland origin, e.g. tubular, cribriform and solid architecture
- Biphasic ductal and myoepithelial differentiation may be evident on H&E and on immunostain for myoepithelial markers (e.g. calponin, S100, SOX10 and smooth muscle actin)
- Areas showing definite squamous differentiation may be seen in the forms of true keratinization, keratin pearls and intracellular bridges
- Focally, the tumor may show basaloid features resembling cylindroma with peripheral palisading and high nuclear to cytoplasmic ratio, as well as tumor forming solid nests and lobules separated by hyalinized fibrous bands
- Surface involvement with marked nuclear pleomorphism may be seen in about 70% of cases
- At high power, typically shows randomly distributed tumor cells with marked nuclear pleomorphism and hyperchromasia
Other rare features that may be seen
- Areas with pure sarcomatoid / spindle cell proliferation with or without dilated staghorn shaped vasculature
- Heterologous mesenchymal component e.g. chondroid or osseous differentiation

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Surface involvement

Spindle cell area

Cribriform architecture

Tubular pattern

Basaloid area

Basaloid area with peripheral palisading

Resembling adenoid cystic carcinoma

Squamous differentiation

Calponin

SMA

p16

S100

p40

Positive stains

p16 consistently shows diffuse and strong nuclear and cytoplasmic staining
Myoepithelial differentiation by immunohistochemistry, i.e. it is typically positive for myoepithelial markers, e.g. calponin, S100 and smooth muscle actin
Also shows squamous differentiation by immunohistochemistry, i.e. it is typically positive for p40, p63 and high molecular weight cytokeratin (e.g. CK5 / 6 and 34βE12)
MYB immunohistochemistry can be positive (although negative for MYB fusion by FISH) (Head Neck Pathol 2019;13:220)
INI1 (retained)

Negative stains

Melanocytic markers, e.g. melanA and HMB45
Neuroendocrine markers, e.g. synaptophysin, chromogranin and INSM1

Molecular / cytogenetics description

All reported cases are positive for high risk HPV using various detection methods, e.g. DNA in situ hybridization (ISH), RNA ISH and PCR based essays
EBV ISH (EBER)
Does not have any characteristic molecular or cytogenetic findings
Consistently negative for fusions characteristics for adenoid cystic carcinoma, e.g. MYB, MYBL1 and NFIB (Am J Surg Pathol 2017;41:1690)

Molecular / cytogenetics images

Contributed by Bin Xu, M.D., Ph.D.

RNA-ISH positive for HPV

Sample pathology report

Nasal cavity, left, resection:
- HPV related multiphenotypic sinonasal carcinoma (see comment)
- Comment: The tumor shows biphasic differentiation with ductal and myoepithelial cells arranged as tubular, cribriform and solid architecture. There are scattered tumor cells with marked nuclear pleomorphism. There is surface involvement. Immunohistochemistry studies show that the tumor is positive for S100, SMA, calponin and p16 (diffuse and strong nuclear and cytoplasmic). RNA in situ hybridization for high risk HPV is positive in this tumor. The overall histologic features and immunophenotype are consistent with the above diagnosis. In the current WHO classification (4th edition), HPV related multiphenotypic sinonasal carcinoma is considered as a provisional diagnosis in the category of sinonasal squamous cell carcinoma (Am J Surg Pathol 2017;41:1690).

Differential diagnosis

Adenoid cystic carcinoma:
- No confirmed association with HPV infection (Am J Surg Pathol 2017;41:1422)
- 60 - 80% positive for MYB / MYBL1 / NFIB translocation
- Both HPV related multiphenotypic sinonasal carcinoma and adenoid cystic carcinoma can show
  - Biphasic differentiation with ductal and myoepithelial elements
  - Immunopositivity for myoepithelial markers (e.g. calponin, smooth muscle actin and S100)
  - Tubular, cribriform and solid architecture
  - Squamous differentiation (in adenoid cystic carcinoma with high grade transformation) (Am J Surg Pathol 2007;31:1683)
Sinonasal squamous cell carcinoma:
- 15 - 30% can be positive for high risk HPV (Am J Surg Pathol 2013;37:185)
- Lacks biphasic or myoepithelial differentiation by histology and immunohistochemistry
- Both tumors can have squamous differentiation
SMARCB1 deficient sinonasal carcinoma:
- HPV negative
- SMARCB1 (INI1) loss by immunohistochemistry
- Both tumors can have basaloid features and squamous differentiation
Sinonasal undifferentiated carcinoma (SNUC):
- HPV negative
- Diagnosis of exclusion, i.e. the diagnosis can only be made when any specific diagnostic entity (e.g. HPV related multiphenotypic sinonasal carcinoma) has been excluded

Board review style question #1

A 45 year old man is present with a nasal cavity mass. A representative H&E of the mass is shown in the picture. Which of the following statements is true?

Differential diagnoses include adenoid cystic carcinoma of salivary gland origin and HPV related multiphenotypic sinonasal carcinoma
Tumor is consistently negative for myoepithelial markers, e.g. SMA, calponin and S100
Tumor may be positive for EBV
80% are positive for EWSR1 fusion

Board review style answer #1

A. Differential diagnoses include adenoid cystic carcinoma of salivary gland origin and HPV related multiphenotypic sinonasal carcinoma

Comment here

Reference: HPV related multiphenotypic sinonasal carcinoma

Board review style question #2

Which of the following statements is true for HPV related multiphenotypic sinonasal carcinoma?

May contain areas resembling adenoid cystic carcinoma
May show neuroendocrine differentiation
Related with low risk HPV, e.g. type 6 and 11
Typically negative for p40, p63 and high molecular weight cytokeratin

Board review style answer #2

A. May contain areas resembling adenoid cystic carcinoma

Comment here

Reference: HPV related multiphenotypic sinonasal carcinoma

Inflammatory sinonasal polyp

Table of Contents

Definition / general

Benign, nonneoplastic inflammatory outgrowth of sinonasal mucosa
Most common type of sinonasal polyp
Most common space occupying lesion of the sinonasal tract (J Clin Diagn Res 2014;8:FC04)

Essential features

Benign, nonneoplastic polyp characterized by edematous stroma infiltrated by mixed inflammatory cells

Terminology

Chronic rhinosinusitis with nasal polyps
Nasal polyps

ICD coding

ICD-10: J33.9 - nasal polyp, unspecified

Epidemiology

Occurs in 2 - 10% of population (J Allergy Clin Immunol Pract 2021;9:4117, StatPearls: Nasal Polyps [Accessed 12 January 2022])

Sites

Commonly bilateral and multifocal (Pak J Med Sci 2020;36:146)
Most frequently involves nasal cavity and ethmoid sinus (J Allergy Clin Immunol Pract 2016;4:565)

Pathophysiology

Defected epithelial cell barrier, increased exposure to bacteria and dysfunctioning host immune system may play a role in the pathogenesis (J Allergy Clin Immunol Pract 2016;4:565)

Etiology

Most frequently occurs in the setting of chronic rhinosinusitis
Other risk factors include allergy, systemic vasculitis, cystic fibrosis, sensitivity to aspirin and nonsteroid anti-inflammatory drugs (StatPearls: Nasal Polyps [Accessed 12 January 2022])

Clinical features

Most common symptoms: obstruction, nasal congestion, rhinorrhea, facial pressure and pain (J Allergy Clin Immunol Pract 2016;4:565)

Diagnosis

Diagnosis can be rendered based on the typical endoscopic or histologic findings

Radiology description

Smooth soft tissue masses commonly originate in the ethmoid sinuses and protrude into the nasal cavity (Eur Radiol 2006;16:872)
Hypodense but may be hyperdense due to concurrent fungal infection or increased protein content
May demonstrate adjacent bony remodeling or erosion

Radiology images

Images hosted on other servers:

Coronal CT

Prognostic factors

Recurrence rate is approximately 60% in patients followed for at least 10 years
Presence of asthma is associated with increased risk of recurrence
Reference: Am J Rhinol Allergy 2021;35:449

Case reports

21 and 32 year old men with infarcted angiomatous nasal polyps (Eur Arch Otorhinolaryngol 2005;262:225)
4 cases of angiomatous nasal polyps (Cureus 2020;12:e7642)

Treatment

Medical treatments include nasal corticosteroid and high volume saline irrigation (JAMA 2015;314:926)
Sinus surgery for patients failed medical management (J Allergy Clin Immunol Pract 2016;4:565)

Clinical images

Images hosted on other servers:

Translucent polyps with a smooth surface

Gross description

Usually multiple and bilateral and involve nasal cavity and paranasal sinuses
Have translucent, moist or edematous cut surface
Broad base of attachment is present
Usually not destructive

Microscopic (histologic) description

Edematous, fibrotic or loosely myxoid stroma covered by respiratory epithelium
Infiltrated by mixed inflammatory cells, including lymphocytes, plasma cells, eosinophils, neutrophils and mast cells
Surface epithelium can show ulceration or squamous metaplasia
May have bizarre stromal cells (large and pleomorphic)
Submucosal glands are decreased or absent
Concurrent fungal infection may be seen
Rarely, osseous metaplasia may be present

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Edematous stroma

Mixed inflammatory infiltrate

Respiratory epithelium lining

Surface ulceration, squamous metaplasia

Stroma with hemorrhage

Infarction

Sample pathology report

Nasal cavity, left, excision:
- Inflammatory sinonasal polyp

Differential diagnosis

Sinonasal papilloma:
- Inflammatory polyp lacks the epithelial proliferation, the thickened epithelial lining or the inverted growth pattern seen in sinonasal papilloma
Respiratory epithelial adenomatoid hamartoma:
- Inflammatory polyp lacks the proliferation of respiratory epithelium and thickened basement membrane typical of respiratory epithelial adenomatoid hamartoma
Biphenotypic sinonasal sarcoma:
- Can be polypoid but characterized by cellular spindle cells in the stroma showing biphenotypic neural and myoid differentiation
Rhabdomyosarcoma, embryonal (botryoid) type:
- Can be polypoid but occurs in pediatric population and has a cambium layer of cellular small, blue, round cells showing skeletal muscle differentiation (i.e., positive for myogenin or MyoD1)

Board review style question #1

What is the most common polypoid lesion in the sinonasal cavity?

Angiofibroma
Inflammatory sinonasal polyp
Respiratory epithelial adenomatoid hamartoma
Sinonasal papilloma

Board review style answer #1

B. Inflammatory sinonasal polyp is the most common polypoid lesion and space occupying lesion in the sinonasal tract.

Comment Here

Reference: Inflammatory sinonasal polyp

Board review style question #2

What is the diagnosis of this lesion excised from the left nasal cavity of a 35 year old woman?

Biphenotypic sinonasal sarcoma
Inflammatory sinonasal polyp
Inverted sinonasal papilloma
Respiratory epithelial adenomatoid hamartoma

Board review style answer #2

B. This is an inflammatory sinonasal polyp, a nonneoplastic benign lesion characterized by edematous stroma and inflammatory infiltrates.

Comment Here

Reference: Inflammatory sinonasal polyp

Intestinal type

Table of Contents

Definition / general

Sinonasal intestinal type adenocarcinoma (ITAC) is an epithelial tumor of the nasal cavity and the paranasal sinuses, often related to professional exposure to organic dust (such as wood or leather) and histologically resembling intestinal adenocarcinoma (Head Neck 2016;38:1564)
ITACs can be present in 5 morphologic patterns: colonic, papillary, solid, mucinous and mixed (Head Neck Pathol 2017;11:295)

Essential features

Incidence is correlated with organic dust exposure (Cancers (Basel) 2021;13:5245)
ITAC is usually located in the olfactory mucosa of the ethmoid sinus (Cancers (Basel) 2021;13:5022)
A characteristic feature of this tumor is an increased production of intracellular or extracellular mucin, similar to mucinous adenocarcinoma of the intestinal tract (Cancers (Basel) 2021;13:5022)

Terminology

Colloid type adenocarcinoma, colonic type adenocarcinoma, enteric type adenocarcinoma (these terms are not recommended for use by WHO)

ICD coding

ICD-O: 8144/3 - intestinal type adenocarcinoma
ICD-11:
- 2C20.0 & XH0349 - adenocarcinoma of nasal cavity & adenocarcinoma, intestinal type
- 2C22.0 & XH0349 - adenocarcinoma of accessory sinuses & adenocarcinoma, intestinal type

Epidemiology

Male predominance (M:F ratio can vary from 4:1 to 21:1 in different geographical regions) with a median age of 60 - 65 years (Cancers (Basel) 2021;13:5245, Head Neck 2016;38:1564)
Strong correlation to professional exposure to organic dust, such as wood or leather (Head Neck 2016;38:1564)
Incidence of ITAC varies between geographical regions, presumably due to differences in dust exposure (Cancers (Basel) 2021;13:5245)
Reported average exposure period is ~40 years
In contrast to squamous cell carcinoma of a similar region, alcohol, smoking and human papillomavirus do not seem to be risk factors for the development of ITAC (Head Neck 2016;38:1564)

Sites

Most common location is the olfactory mucosa of the ethmoid sinus but can occur in the nasal cavity and maxillary antrum (Cancers (Basel) 2021;13:5022)
Cases related to industrial wood dust exposure show predilection for ethmoid sinus
Sporadic tumors are more common in maxillary antrum

Pathophysiology

ITAC is considered to develop through intestinal metaplasia of the sinonasal epithelium (Patholog Res Int 2011;2011:230147)
Wood dust does not seem to have direct mutagenic properties of its own but prolonged exposure to and irritation by wood dust particles can stimulate cellular turnover by inflammatory pathways
Chronic inflammation is recognized as an important mechanism in tumor initiation and progression (Head Neck 2016;38:1564)

Etiology

Exposure to organic dust (such as wood or leather) for several decades is the major risk factor (Head Neck 2016;38:1564)

Clinical features

Unilateral nasal obstruction, rhinorrhea, epistaxis are common presentations (Arch Craniofac Surg 2018;19:210)
Tumor tends to be very locally aggressive but rarely metastasizes (Arch Craniofac Surg 2018;19:210, Pathol Res Pract 2019;215:152432)
Advanced tumors may cause pain, neurologic disturbances, exophthalmos, visual impairment

Diagnosis

CT and MRI are used for diagnosing early lesions, defining disease extent and detecting early recurrences
Ultrasound guided fine needle aspiration plays an important role in confirming the diagnosis before treatment because it is frequently misdiagnosed as a salivary gland tumor (Arch Craniofac Surg 2018;19:210)

Radiology description

CT or MRI may reveal soft tissue mass in the ethmoid sinus, frontal sinus or other locations (Arch Craniofac Surg 2018;19:210)

Radiology images

Images hosted on other servers:

Frontoethmoidal sinus mass

Frontal sinus mass

Prognostic factors

Locally aggressive with ~50% local recurrence
Locoregional / distant metastasis occurs in 10 - 20% cases
Mean disease free survival is 32 months (Cancers (Basel) 2021;13:5022)
Papillary subtype is associated with better prognosis, while mucinous and solid subtypes carry poor prognosis (Cancers (Basel) 2021;13:5022)
Prognosis and response to the chemotherapy can be associated with genotoxic agents, such as TP53 mutations
- Significantly higher complete response rate and disease free survival rate were reported in patients carrying tumors with wild type TP53 compared to patients bearing mutated TP53 (Head Neck 2016;38:1564)
There is no significant prognostic difference between occupational and sporadic tumors

Case reports

36 year old man with ITAC that developed from inverted papilloma (J Clin Diagn Res 2016;10:ED12)
50 year old man with right nasal block, mass in right nose and frontal headache (J Clin Diagn Res 2014;8:149)
63 year old man with a rapidly growing soft mass on his glabellar region for 4 months (Arch Craniofac Surg 2018;19:210)

Treatment

Standard treatment is surgical resection, with a minimally invasive endoscopic approach when possible (Cancers (Basel) 2021;13:5022)
Due to the high recurrence rate of ITAC, postoperative radiation is commonly administered
- Neoadjuvant chemotherapy is used in advanced stage tumors (Cancers (Basel) 2021;13:5022)
Because local recurrences and metastases of these tumors occur frequently, palliative treatment is most often the only option (Head Neck 2016;38:1564)

Clinical images

Images hosted on other servers:

Mass on glabellar region

Wide excision of mass

76 days after surgery

Endoscopic resection

Gross description

Irregular exophytic tan-pink mass bulging into nasal cavity or paranasal sinuses, often with necrotic and friable appearance
Some lesions are gelatinous

Gross images

Contributed by Kelly Magliocca, D.D.S., M.P.H.

Macroscopic appearance

Images hosted on other servers:

Open biopsy masses

Microscopic (histologic) description

ITACs can be present in 5 morphologic patterns: colonic, papillary, solid, mucinous and mixed (Head Neck Pathol 2017;11:295)
Papillary pattern: predominantly papillary growth with tubular elements
Colonic pattern: tubuloglandular architecture with minor papillary elements; neoplastic cells have palisaded hyperchromatic nuclei and a few goblet cells
Solid pattern: poorly differentiated; trabecular and solid proliferation of neoplastic cells
Mucinous pattern: mucin laden neoplastic glands or tumor cell clusters within pools of extracellular mucin
Mixed pattern: variable admixture of 2 or more subtypes
Goblet cells, Paneth cells and argentaffin cells may be found in all patterns
Exceptionally well differentiated ITAC may resemble normal small intestinal mucosa with well formed villi and muscularis mucosae

Microscopic (histologic) images

Contributed by Vladyslav Ilchenko, M.D., Diana Bell, M.D. and Kelly Magliocca, D.D.S., M.P.H.

Complex glands

Papillary pattern with goblet cells

Tubuloglandular architecture

Complex colonic type glands and stroma

Mucinous type

CK20

CDX2

Positive stains

Consistently positive for CK20, CDX2, villin, MUC2, SATB2 (Head Neck Pathol 2022;16:670)
Variably positive for CK7 and CEA
Chromogranin+ cells may be present, scattered or in clusters

Molecular / cytogenetics description

Frequent KRAS and p53 mutations (Head Neck Pathol 2022;16:670, Head Neck 2016;38:1564)
Tumors with occupational exposure to wood dust show p53, p14 ARF, p16 INK4a gene deregulation
EGFR alterations also reported (Cancers (Basel) 2021;13:5022)
Mutations in the genes in Wnt, MAPK and PI3K pathways were reported in 20%, 20% and 24% of cases, respectively (Cancers (Basel) 2021;13:5022)

Videos

Update on sinonasal carcinoma

Malignant tumors of the paranasal sinuses

Sample pathology report

Ethmoid sinus, biopsy:
- Invasive adenocarcinoma, intestinal type (see comment)
- Comment: The patient's clinical history of a mass in the right ethmoid sinus is noted. Morphology and immunophenotypic features (positive for CK7, CK20, villin and MUC2) are most consistent with intestinal type sinonasal adenocarcinoma. However, a metastasis from elsewhere, particularly the digestive tract, cannot be absolutely ruled out. Clinical and imaging correlation is suggested.

Differential diagnosis

Nonintestinal sinonasal adenocarcinoma:
- Usually not associated with wood dust exposure
- Clean background, may have papillary / tubular architecture
- More glandular, less papillary, few columnar / goblet cells
- Typically negative for intestinal markers, such as CDX2 and SATB2
Metastasis from colonic adenocarcinoma:
- Rare but most important differential
- Usually CEA+, CK7-, chromogranin-
- Clinical features and colonoscopy are helpful
Papillary sinusitis:
- May have abundant mucinous material but has short and blunt papillae with clean background
- Thick and hyalinized basement membrane
- Ciliated surface cells
- Prominent eosinophils and no significant cytological atypia

Board review style question #1

A 70 year old man presented with a mass in the right nose and a frontal headache. A representative image of the mass is shown in the image above. Which of the following statements is true?

Chemotherapy is the standard treatment
Cigarette smoking is the number one risk factor for this tumor
The tumor can be locally aggressive but rarely metastasizes
The tumor is most commonly located in the nasal cavity

Board review style answer #1

C. The tumor can be locally aggressive but rarely metastasizes. The image depicts intestinal type adenocarcinoma, with colonic type morphology. These tumors are known to be locally aggressive but metastasis is very uncommon (answer C). Ethmoid sinus is the most common location, not nasal cavity (answer D). Exposure to organic wood dust is considered as a strong risk factor. Unlike squamous cell carcinoma, cigarette smoking or human papillomavirus is not etiologically linked to ITAC (answer B). Surgical resection is the standard treatment, not chemotherapy (answer A).

Comment Here

Reference: Intestinal type adenocarcinoma

Board review style question #2

Which of the following statements is true for intestinal type sinonasal adenocarcinoma?

Signet ring cell morphology is the most common histologic pattern
Tumor cells have uniform nuclei with salt and pepper chromatin
Tumor may be positive for EBV
Tumor usually demonstrates positive staining for CK20, villin or SATB2

Board review style answer #2

D. Tumor usually demonstrates positive staining for CK20, villin or SATB2. ITAC shows intestinal phenotype and shows immunoreactivity for CK20, villin and SATB2 (answer D). There is no association with EBV (answer C). Common histologic subtypes include colonic, papillary, solid, mucinous and mixed patterns. Signet ring cell morphology is uncommon (answer A). Salt and pepper nuclear chromatin is characteristically observed in neuroendocrine tumors and not in ITAC (answer B).

Comment Here

Reference: Intestinal type adenocarcinoma

Invasive fungal rhinosinusitis

Table of Contents

Definition / general

Acute aggressive life threatening invasive fungal infection involving sinonasal tract and adjacent organs (such as orbit or brain); the mortality rate is ~50% (Laryngoscope 2013;123:1112)

Essential features

Definite diagnosis is made on biopsy by identifying the essential histologic feature, which is invasion of tissue and vessels by fungal organisms, often associated with tissue necrosis and infarction
Mostly occurs in immunocompromised hosts, although immunocompetent patients may also be affected (Laryngoscope 2013;123:1112, Radiographics 2022;42:2075)
Caused by a diverse group of fungal organisms, most commonly Zygomycetes (such as Mucor and Rhizopus) and Aspergillus (Laryngoscope 2013;123:1112, Radiographics 2022;42:2075)
1 of the 3 pathologic manifestations of fungi in the sinonasal tract; the other 2 are allergic fungal sinusitis and mycetoma (fungus ball)

Terminology

Acute invasive fungal (rhino)sinusitis
Angioinvasive fungal (rhino)sinusitis

ICD coding

ICD-10
- J01.90 - acute sinusitis, unspecified
- B49 - unspecified mycosis
- B44 - aspergillosis
- B46 - zygomycosis

Epidemiology

Mostly occurs in immunocompromised patients
Underlying risk factors in a descending order of frequency include (Laryngoscope 2013;123:1112)
- Diabetes (in ~50%), including those with ketoacidosis
- Hematologic malignancy (in ~40%), such as acute lymphoblastic leukemia and acute myeloid leukemia
- Corticosteroid medication
- Renal / liver failure
- Organ transplant (solid organ or allogeneic stem cell transplant)
- HIV / AIDS
- Anaplastic anemia
- Autoimmune disease
May occur in pediatric patients (J Pediatric Infect Dis Soc 2017;6:S22, Int J Pediatr Otorhinolaryngol 2016;90:231)

Sites

Sinonasal tract
Adjacent vital organs, including orbit (in ~50%), intracranial and hard palate (in ~20%) and cavernous sinus (in 9%) (Laryngoscope 2013;123:1112)

Etiology

Immunocompromised host
Caused by hyphae form fungi, commonly Zygomycetes (such as Rhizopus and Mucor) and Aspergillus
Coinfection with COVID-19 and post-COVID-19 infection were reported during COVID-19 pandemic (Laryngoscope Investig Otolaryngol 2022;7:913)

Clinical features

Most common symptoms presenting in > 50% of patients include facial swelling, fever, nasal congestion and ophthalomoplegia (Laryngoscope 2013;123:1112)
Other symptoms include proptosis, vision loss, nasal discharge, facial pain, headache, cranial nerve palsy, altered mental status and palatal necrosis / ulcer

Diagnosis

Diagnosis of invasive fungal rhinosinusitis is rendered on tissue biopsy by identification of fungal hyphae in tissue (such as mucosa, submucosa, bone or vessels)
Tissue culture is recommended for genus of the fungi and antifungal susceptibility testing (Lancet Infect Dis 2019;19:e405, Clin Infect Dis 2016;63:e1)
In situ hybridization and RT-PCR for various fungi can be used in formalin fixed tissue for genus of the fungi

Radiology description

Mucosal thickening
Soft tissue invasion into adjacent tissue / organ(s), such as orbit and intracranial extension

Radiology images

Images hosted on other servers:

Mucosal thickening

Advanced manifestations

Extrasinonasal extension

Prognostic factors

Unfavorable prognostic factors include older age, altered mental status, underlying conditions of anaplastic anemia or renal / liver failure, intracranial or cavernous sinus involvement, neutropenia and treatment delay (Laryngoscope 2013;123:1112, Otolaryngol Head Neck Surg 2018;159:386)
Favorable prognostic factors are surgery and liposomal amphotericin B antifungal therapy

Case reports

27 year old woman with acute lymphoblastic leukemia developed rhinosinusitis after induction chemotherapy (Clin Hematol Int 2022;4:60)
29 year old man post-bone marrow transplant with psychosis and a gingival lesion (Arch Pathol Lab Med 2000;124:883)
33 year old male intranasal cocaine user presented with facial and nasal pain and was found to have invasive Aspergillus flavus sinusitis (IDCases 2021;26:e01327)
36 year old woman, 45 year old woman and 62 year old man with acute invasive fungal sinusitis associated with COVID-19 infection (Indian J Otolaryngol Head Neck Surg 2022;74:3359)

Treatment

Combination of surgery and antifungal treatment (Laryngoscope 2013;123:1112)
- Surgery can be performed via endoscopic or open approach
- The most common antifungal treatment is amphotericin B
Correcting the source of immunosuppression may also be useful

Clinical images

Images hosted on other servers:

Periorbital swelling

Palatal ulceration

Gross description

Necrotic and hemorrhagic tissue fragments

Frozen section description

Fungal hyphae in tissue are diagnostic for invasive fungal sinusitis on frozen sections
Free floating fungal elements with or without mucus, blood, debris or fibrin are insufficient to confirm the invasive nature of the fungi and are therefore insufficient for the diagnosis

Frozen section images

Contributed by Bin Xu, M.D., Ph.D.

Fungal hyphae in tissue

Microscopic (histologic) description

Fungal hyphae in mucosa, submucosa, vessels and bone
- Zygomycetes: broad nonseptate hyphae branching at 90 degrees
- Aspergillus: slender septate hyphae branching at 45 degrees
- Preoperative antifungal treatment may significantly alter the morphology of the hyphae
- Classification of the fungal genus is not reliable on histology: tissue fungal culture or RT-PCR test using paraffin blocks are more reliable tools
Often associated with tissue necrosis, acute inflammation, ulceration or granulation tissue
Grocott-Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains are useful special stains to highlight fungal organisms

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D. and Kelly Magliocca, D.D.S., M.P.H. (Case #493)

Fungal hyphae invade tissue

Angioinvasion

Angioinvasion and necrotic wall

Tissue necrosis

Necrotic and adjacent viable sinonasal mucosa

Ossified cartilage
and adjacent
viable sinonasal
mucosa

Angioinvasion

GMS: 90 degree branching

GMS stain

PAS stain

Cytology description

Cytology (such as nasal swab) can only detect the presence of fungal hyphae
Invasive nature of the fungal elements cannot be established in cytologic samples

Positive stains

GMS and PAS stains

Sample pathology report

Maxillary sinus, biopsy:
- Invasive and angioinvasive fungal rhinosinusitis associated with tissue necrosis, acute inflammation and ulceration (see comment)
- Comment: GMS and PAS stains highlight fungal hyphae.

Differential diagnosis

Key differential diagnosis is noninvasive fungal infection of the sinonasal tract, including
- Allergic fungal sinusitis:
  - Characterized by pools of allergic mucin (i.e., mucin admixed with eosinophil rich inflammation or Charcot-Leyden crystals)
  - Fungal hyphae may be seen in mucin on GMS and PAS stains
  - Tissue invasion by fungi is absent
- Mycetoma (fungus ball):
  - Mass forming growth of densely packed fungal hyphae in sinus cavity
  - Tissue invasion by fungi is absent

Board review style question #1

A child with acute myeloid leukemia develops acute facial swelling, sinus discharge and fever. A nasal turbinate biopsy is taken. What is the diagnosis?

Allergic fungal sinusitis
Granulomatosis with polyangiitis
Invasive fungal sinusitis
Mycetoma

Board review style answer #1

C. Invasive fungal sinusitis. The H&E shows invasive fungal infection with fungal hyphae in a blood vessel and fibrous tissue (i.e., invasive fungal sinusitis). Answers A and D are incorrect as both are noninvasive fungal diseases. Answer B is incorrect because the presence of fungal organisms excludes the diagnosis of granulomatosis with polyangiitis.

Comment Here

Reference: Invasive fungal rhinosinusitis

Board review style question #2

What is the most common causal fungal organism for invasive fungal sinusitis?

Candida albicans
Cryptococcus
Histoplasma capsulatum
Mucor

Board review style answer #2

D. Mucor. The most common causal fungal organisms for invasive fungal sinusitis are Zygomycetes (such as Mucor and Rhizopus) and Aspergillus. Answers A - C are incorrect because Cryptococcus, Histoplasma and Candida are all fungal organisms but are not the common cause for invasive fungal sinusitis.

Comment Here

Reference: Invasive fungal rhinosinusitis

Low grade nasopharyngeal papillary adenocarcinoma

Table of Contents

Definition / general

Low grade primary adenocarcinoma of nasopharynx

Essential features

Relatively rare nasopharyngeal tumor
No known etiologic agents; lacks Epstein-Barr virus (EBV) association
Morphologically, an adenocarcinoma with predominant papillary architecture and hyalinized cores
Mimics papillary thyroid carcinoma; may be TTF1+, however, PAX8- and thyroglobulin-
Excellent prognosis with no known metastases

Terminology

Thyroid-like low grade nasopharyngeal papillary adenocarcinoma
Low grade nasopharyngeal papillary adenocarcinoma

ICD coding

ICD-10: C11.9 - malignant neoplasm of nasopharynx, unspecified

Epidemiology

Uncommon tumor of nasopharynx (Ear Nose Throat J 2017;96:456)
< 1% of nasopharyngeal malignancies
Median age of 37 years but occurs over a wide age range (reported range: second - seventh decade)
No gender predilection

Sites

May occur anywhere in nasopharynx but common locations are roof, posterior wall and lateral wall of nasopharynx

Pathophysiology

Exact pathogenesis is unclear

Etiology

No known etiologic agents
Not associated with wood dust exposure or other known factors
Lacks any EBV or human papillomavirus (HPV) association
Association with Turner syndrome in a rare case (Med J Malaysia 1998;53:104)

Clinical features

Nasal obstruction is the most common presenting symptom (Am J Clin Pathol 2019;152:582)
Tumors usually remain confined within the nasopharynx
Subset of patients with tumor involving the posterior and lateral nasopharyngeal walls present with otitis media or postnasal drip
Slow growing and indolent

Diagnosis

Imaging followed by biopsy

Radiology description

Nasopharyngeal endoscopy typically reveals polypoid or pedunculated masses
Sinus computed tomography (CT) images show circular or nodular mass at the nasopharynx or the edge of the nasal septum, moderately to strongly enhancing on contrast enhanced CT (CECT) with no bone destruction (Cancer Manag Res 2021;13:1271)
Sinus magnetic resonance imaging (MRI) reveals masses with moderate signals in plain T1 weighted images and strong signals in T2 weighted images

Radiology images

Images hosted on other servers:

Pedunculated tumor without bone destruction

Prognostic factors

Excellent prognosis with complete surgical excision
Rarely recurs (if incomplete excision)
No metastases reported to date (Ear Nose Throat J 2017;96:456)

Case reports

22 year old woman with nasopharyngeal papillary adenocarcinoma harboring a ROS1::GOPC fusion (Medicine (Baltimore) 2021;100:e24377)
42 year old nonsmoking woman presented with foreign body sensation in pharynx and dry throat for 1 month (Transl Cancer Res 2020;9:4457)
50 year old woman harboring biphasic thyroid-like low grade nasopharyngeal papillary adenocarcinoma with a prominent spindle cell component (Diagnostics (Basel) 2020;10:323)

Treatment

Complete surgical excision is usually curative
Some patients may receive radiation, though role of radiotherapy is unclear

Clinical images

Images hosted on other servers:

Well defined large polypoid tumor

Gross description

Soft, exophytic mass with papillary, polypoidal or nodular appearance (Ear Nose Throat J 2017;96:456)
Size can vary from a few millimeters to 3 cm
Consistency may be soft or gritty

Microscopic (histologic) description

Invasive tumor involving surface epithelium, at times merging with adjacent nonneoplastic epithelium
Papillary and glandular growth patterns (Cancer Manag Res 2021;13:1271)
- Papillary structures are complex with arborization and hyalinized fibrovascular cores
- Glandular growth pattern has cribriform or back to back glands
Lined by single layer of cuboidal to columnar cells with moderate amount of eosinophilic cytoplasm and round to oval nuclei
Nuclei are vesicular or optically clear showing grooves or membrane irregularities mimicking papillary thyroid carcinoma
Mild to moderate nuclear pleomorphism, no / rare nucleoli
Mitotic figures are inconspicuous
Psammoma bodies may be present in 33% of cases
Necrosis is rare and usually absent
No angiolymphatic invasion or perineural invasion

Microscopic (histologic) images

Contributed by Diana Bell, M.D. and Lester Thompson, M.D.

Tumor underneath nasopharyngeal mucosa

Tumor infiltrating underlying stroma

Interwoven papillae and glands

Papillae lined by columnar cells

Nuclear overlapping

Nuclear features mimicking PTC

Pseudoinclusions and nuclear clearing

Psammoma bodies

TTF1 IHC

Thyroglobulin IHC

Positive stains

PAS (intracytoplasmic, diastase resistant granules), mucin stains like mucicarmine (intracellular or luminal)
Pancytokeratin (diffuse), CK7 (diffuse), EMA (diffuse), CK5/6, CEA (focal), CK19 (subset of cases), S100 (focally in few cases) (Cancer Manag Res 2021;13:1271)
TTF1 (J Formos Med Assoc 2015;114:473)
Low proliferation indices (Ki67 < 5%)

Negative stains

PAX8, thyroglobulin, CK20, CDX2, villin, GFAP, BCL2 (Hum Pathol 2023;134:66)
EBV encoded small nuclear RNA in situ hybridization

Molecular / cytogenetics description

No defined genetic alterations to date
No BRAF or NRAS mutations
One case was reported in a patient with Turner syndrome (Med J Malaysia 1998;53:104)
ROS1 gene rearrangements with presence of ROS1::GOPC fusion has been described in a patient (Medicine (Baltimore) 2021;100:e24377)

Sample pathology report

Roof of nasopharynx, endoscopic resection:
- Nasopharyngeal papillary adenocarcinoma (1 cm) (see comment)
- Margins negative
- Comment: Microscopic examination reveals complex, interwoven papillary architecture along with crowded back to back glands. The tumor nuclei are oval and exhibit mild degree of pleomorphism with presence of optically clear chromatin. Lymphovascular or perineural invasion are not identified. On immunohistochemistry, the tumor cells are immunopositive for pan-CK, CK7 and TTF1, while they are negative for PAX8 and thyroglobulin. The findings are consistent with nasopharyngeal papillary adenocarcinoma.

Differential diagnosis

Metastatic papillary thyroid carcinoma:
- No surface epithelial dysplasia
- PAX8+ and thyroglobulin+
- TTF1+ in both tumor types (Head Neck Pathol 2019;13:661)
Sinonasal intestinal type adenocarcinoma, papillary variant:
- Nasal cavity and paranasal sinuses
- Usually wood dust exposure
- More papillary and less glandular
- Tall columnar and goblet cells
- Lack of nuclear features of papillary thyroid carcinoma
- Dirty background with hemorrhage and inflammation
- Mitotic activity
- Usually positive for CK20, CDX2, villin and MUC2 (Ann Diagn Pathol 2006;10:215)
Polymorphous adenocarcinoma of salivary gland origin:
- Rare in nasopharynx
- Arises from minor salivary glands in submucosa, not surface epithelium
- Diverse architectural patterns
- Aggressive with local recurrence (27%) and nodal metastases (17%)
- Usually positive for S100, whereas negative for TTF1
Papilloma of surface epithelial or minor salivary gland origin:
- Lacks infiltrative growth pattern

Board review style question #1

Low grade nasopharyngeal papillary adenocarcinoma

A 45 year old woman presented with a nasopharyngeal mass. Based on the H&E and immunohistochemistry (TTF1) images above, what is the diagnosis?

Low grade nasopharyngeal papillary adenocarcinoma
Metastasis from papillary thyroid carcinoma
Polymorphous adenocarcinoma
Sinonasal intestinal type adenocarcinoma, papillary variant

Board review style answer #1

A. Low grade nasopharyngeal papillary adenocarcinoma. The pictures show a tumor arranged as glands and interwoven papillae with hyalinized cores. The tumor nuclei show pseudoinclusions, nuclear clearing, longitudinal grooves and overlapping. No mitotic figures are identified. Diffuse nuclear immunopositivity for TTF1 is seen. These features are consistent with a low grade nasopharyngeal papillary adenocarcinoma. Though metastasis from papillary thyroid carcinoma is also TTF1 positive and shows similar nuclear features, answer B is incorrect because it does not fit the given clinical history of presence of only a nasopharyngeal mass. However, in case of diagnostic dilemma, other immunohistochemical markers like PAX8 and thyroglobulin can be used, which are immunopositive in papillary thyroid carcinoma but not in low grade nasopharyngeal papillary adenocarcinoma. Answer C is incorrect because polymorphous adenocarcinoma usually shows highly variable architectural patterns in different proportions including solid, trabecular, tubular, reticular, cribiform and papillary arrangements. The tumor cells usually have monotonous pale nuclei and are immunonegative for TTF1. Answer D is incorrect because sinonasal intestinal type adenocarcinoma, papillary variant shows tumor cells arranged in papillary architecture with presence of goblet cells. The tumor cells are immunopositive for CD20 and CDX2, while TTF1 is negative in this tumor.

Comment Here

Reference: Low grade nasopharyngeal papillary adenocarcinoma

Board review style question #2

Regarding low grade nasopharyngeal papillary adenocarcinoma, which of the following statements is true?

Complete surgical excision is usually curative
PAX8 is immunopositive in this tumor
This tumor has EBV association
This tumor has a high rate of metastasis

Board review style answer #2

A. Complete surgical excision is usually curative. This tumor exhibits indolent biological behavior and complete surgical excision is usually curative. Answer C is incorrect because this tumor does not have any known etiological agent or any viral association. Answer B is incorrect as PAX8 (which is a transcription factor involved in development of the central nervous system, eye, kidney, thyroid gland, organs derived from the mesonephric [Wolffian] duct and organs derived from the Müllerian duct) is usually immune negative in nasopharyngeal tumors. Answer D is incorrect because this tumor usually has anexcellent prognosis with no known metastases.

Comment Here

Reference: Low grade nasopharyngeal papillary adenocarcinoma

Nasal chondromesenchymal hamartoma

Table of Contents

Definition / general

Rare; intranasal and paranasal polypoid mass in infants and occasionally older children
2/3 male, mean age 14 months, range 1 day to 7 years
Benign but fills nasal cavity and usually extends into ethmoid sinuses
May erode bone, including cribriform plate and have an intracranial component

Radiology images

Contributed by I Weng Lao, M.D., Ph.D. and Jian Wang, M.D., Ph.D.

CT scan

Case reports

47 year old woman with endoscopic surgery for nasal polyp (Case of the Week #291)

Treatment

Excision

Microscopic (histologic) description

Well demarcated mature cartilage, myxoid stroma, focal osteoclast-like giant cells, aneurysmal bone cyst-like formations, spindle cells, collagen fibers

Microscopic (histologic) images

Contributed by I Weng Lao, M.D., Ph.D. and Jian Wang, M.D., Ph.D.

7 month old infant boy

Case #291

Various images

Positive stains

Electron microscopy description

Fibroblastic and myofibroblastic differentiation

Additional references

Am J Surg Pathol 1998;22:425, Arch Pathol Lab Med 2001;125:400

Nasopharyngeal angiofibroma

Table of Contents

Definition / general

Locally aggressive fibrovascular neoplasm of the nasopharynx developed almost exclusively in adolescent and young male patients

Essential features

Nasopharyngeal location
Affecting adolescent or young male patients
Histologically composed of vasculature of various sizes and cellular fibrotic stroma with fibroblasts

Terminology

Juvenile nasopharyngeal angiofibroma, juvenile fibroma, angiofibroma

ICD coding

ICD-O: 9160/0 - angiofibroma, NOS
ICD-10: D10.6 - benign neoplasm of nasopharynx

Epidemiology

0.05 - 0.5% of all head and neck tumors (StatPearls: Nasopharyngeal Angiofibroma [Accessed 10 June 2020])
Occurs almost exclusively in adolescent and young males, with a median age of diagnosis of 15 years (range: 8 - 27 years) (Acta Otorrinolaringol Esp 2019;70:279, Head Neck Pathol 2018;12:52)
Although a handful of case reports describe nasopharyngeal angiofibroma in female patients, the documentation of these cases is not convincing to represent this particular entity (Mol Clin Oncol 2018;9:702, J Laryngol Otol 2018;132:184, Eur Arch Otorhinolaryngol 2006;263:657, Indian J Dent Res 2004;15:145, AMA Arch Otolaryngol 1951;54:620)
May occur in patients with familial adenomatous polyposis (Gastroenterology 1993;105:1550, Otolaryngol Head Neck Surg 1995;113:435, ANZ J Surg 2013;83:387)

Sites

Arises in the nasopharynx or posterolateral wall of nasal cavity (Otolaryngol Head Neck Surg 2019;161:352)
May be locally aggressive, show extension into paranasal sinus, pterygopalatine fossa, infratemporal fossa and orbit (Otolaryngol Head Neck Surg 2019;161:352)
10 - 37% have intracranial extension, usually into the middle cranial fossa (Otolaryngol Head Neck Surg 2019;161:352, StatPearls: Nasopharyngeal Angiofibroma [Accessed 10 June 2020])

Etiology

Etiology remains unclear
May be hormonally affected given the predilection for adolescent male

Clinical features

Highly vascular lesion with one or more feeding arterials
- The most common feeding vessel is the internal maxillary artery, a branch of the external carotid artery (StatPearls: Nasopharyngeal Angiofibroma [Accessed 10 June 2020])
Most frequently presents with epistaxis followed by nasal obstruction and rhinorrhea (Head Neck Pathol 2018;12:52, J Oral Maxillofac Pathol 2016;20:330)

Diagnosis

Diagnosis is typically rendered using angiography, which allows visualization of the feeding vessels and preoperative embolization
Given the risk of massive hemorrhage, preoperative biopsy and fine needle aspiration is strongly discouraged

Radiology description

Angiography allows identification of a highly vascularized mass with a central feeding vessel

Radiology images

Images hosted on other servers:

Angiography

Prognostic factors

Although considered as a benign mesenchymal neoplasm, nasopharyngeal angiofibroma is locally aggressive with approximately 20% local recurrence (Otolaryngol Head Neck Surg 2019;161:352, J Laryngol Otol 2018;132:978)
Cranial or orbital involvement and postoperative residual vascularity on imaging study are associated with increased risk of local recurrence (Otolaryngol Head Neck Surg 2019;161:352)

Case reports

17 year old boy with nasopharyngeal angiofibroma extending intraorally (J Oral Maxillofac Pathol 2016;20:330)
18 year old man with nasal mass, recurrent epistaxis and nasal obstruction (J Clin Diagn Res 2017;11:MD03)
21 year old man with bilateral nasopharyngeal angiofibroma (Eur Arch Otorhinolaryngol 2016;273:3435)
31 year old man with Proteus syndrome and nasopharyngeal angiofibroma (Hippokratia 2017;21:147)
32 year old man with severe epistaxis and nasopharyngeal mass (BMJ Case Rep 2018)

Treatment

Complete surgical resection is the treatment of choice
Preoperative embolization through angiography may be performed

Clinical images

Images hosted on other servers:

Facial swelling

Gross description

Polypoid firm mass
Color varies from yellow to dark red or black, depending on the extent of intraoperative hemorrhage

Gross images

Contributed by Kelly Magliocca, D.D.S., M.P.H.

Gross appearance, cut surface

Gross appearance with ink

Images hosted on other servers:

Polypoid, beige to brown, firm, fibrotic mass

Microscopic (histologic) description

Benign fibrovascular lesion composed of 2 components
- Vascular space of various sizes, ranging from dilated branching vessel of various thickness to slit-like capillaries
- Fibrous or collagenous stroma with fibroblasts
Central area of the tumor is typically cellular, composed of fibroblasts or myofibroblasts with spindle, round or stellate morphology
Stroma can be fibrous, edematous or collagenized
Fibrinous thrombi may be seen in dilated vessels
Frequently contain (abundant) mast cells
Mitotic figures are usually absent
Reference: Chan: WHO Classification of Head and Neck Tumours, 4th Edition, 2017

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Polypoid mass

Large caliber vessels

Slit-like vasculature

Cellular stroma

Bland fibroblasts

Edematous or collagenized stroma

Beta catenin

Contributed by Kelly Magliocca, D.D.S., M.P.H.

Correlate to "Gross appearance with ink"

Vascular channel, low magnification

Vascular channel, higher magnification

Cytology description

Given the nasopharyngeal location and the highly vascular nature of the lesion, fine needle aspiration should be avoided

Positive stains

SMA, HHF35 / h-caldesmon in smooth muscle wall of large vasculature (Pathology 2008;40:396, Head Neck Pathol 2018;12:52)
CD31, CD34 and ERG highlight endothelial cells of vasculature
AR is positive in stroma cells in 40 - 75% cases; the expression may be focal and weak (Acta Otolaryngol 2015;135:51, Am J Clin Pathol 2006;125:832, Mod Pathol 1998;11:1122)
Reported positive rate of ER is highly variable, ranging from 0% to over 90% partially depending on the subunits stained (Acta Otolaryngol 2015;135:51, Am J Clin Pathol 2006;125:832)
Beta catenin: nuclear staining in stromal cells (fibroblasts) in 70 - 90% of cases, membranous / cytoplasmic staining in endothelial cells (J Laryngol Otol 2016;130:907)

Negative stains

PR and CD117 (Pathology 2008;40:396, Head Neck Pathol 2018;12:52)

Molecular / cytogenetics description

Somatic mutation of CTNNB1 (beta catenin) gene in 75% of cases (Ann Otol Rhinol Laryngol 2019;128:1061)

Sample pathology report

Nasopharynx, resection:
- Nasopharyngeal angiofibroma, 1.8 cm, margin negative for tumor (see comment)
- Comment: Immunostain shows that the tumor is focally positive for AR. There is abnormal nuclear accumulation of beta catenin. The immunoprofile supports the diagnosis.

Differential diagnosis

Hemangioma:
- May affect both genders, any age and is not limited to nasopharynx
- Lacks cellular stroma enriched with fibroblasts
- Vessels are typically uniform in size, whereas angiofibroma usually contains central large caliber vessels and peripheral slit-like vascular space
- Does not show AR immunopositivity or nuclear beta catenin
Inflammatory sinonasal polyp:
- May contain fibrous to edematous stroma but usually hypocellular
- Lack rich vasculature seen in angiofibroma
- Does not show AR immunopositivity or nuclear beta catenin
- Occurs in nasal cavity or paranasal sinuses, rather than nasopharynx
Nasal turbinate:
- Normal nasal turbinate is vascular rich, containing large caliber blood vessels with muscle wall
- Lacks hypercellular stroma and slit-like vasculatures of angiofibroma

Board review style question #1

It is commonly S100+ and desmin+
It is locally aggressive with 20% risk of local recurrence
It is typically diagnosed preoperatively using endoscopic biopsy
It often harbors PAX3 translocation

Board review style answer #1

B. It is locally aggressive with 20% risk of local recurrence

Comment Here

Reference: Nasopharyngeal angiofibroma

Board review style question #2

It generally affects adolescent women
It has a hormonal profile of ER+, PR+, AR+
It is a benign lesion that can be safely managed by long term observation even when large
The most frequent molecular alteration in this lesion is CTNNB1 somatic mutation

Board review style answer #2

D. The most frequent molecular alteration in this lesion is CTNNB1 somatic mutation

Comment Here

Reference: Nasopharyngeal angiofibroma

Nasopharyngeal carcinoma

Table of Contents

Definition / general

Nasopharyngeal carcinoma originates from the nasopharyngeal mucosa showing histologic or immunophenotypic evidence of squamous differentiation
WHO classification of nasopharyngeal carcinoma:
- Nonkeratinizing squamous cell carcinoma
  - Differentiated subtype
  - Undifferentiated subtype
- Keratinizing squamous cell carcinoma
- Basaloid squamous cell carcinoma

Essential features

Originates from nasopharynx
Showing squamous differentiation on H&E or immunohistochemistry
Most are positive for Epstein-Barr virus (EBV) / Epstein-Barr encoded RNA (EBER) in endemic areas (China, Southeast Asia and North Africa)
Nonkeratinizing, undifferentiated subtype is the most common, showing syncytial growth pattern, vesicular nuclei with prominent central nucleoli and reactive lymphoid stroma

Terminology

Nonkeratinizing, undifferentiated: lymphoepithelioma, lymphoepithelial carcinoma, undifferentiated carcinoma
Nonkeratinizing, differentiated: transitional carcinoma
Keratinizing: squamous cell carcinoma

ICD coding

ICD-O:
- 8072/3 - Nonkeratinizing squamous cell carcinoma
- 8071/3 - Keratinizing squamous cell carcinoma
- 8083/3 - Basaloid squamous cell carcinoma
ICD-10:
- C11.9 - Malignant neoplasm of nasopharynx, unspecified

Epidemiology

High Incidence in China, Southeast Asia, North Africa, natives of Arctic region and part of the Mediterranean Basin (Semin Diagn Pathol 2015;32:54, Surg Oncol Clin N Am 2015;24:547)
Rare in US: incidence 0.2 to 0.5 per 100,000 (Semin Diagn Pathol 2015;32:54, Surg Oncol Clin N Am 2015;24:547)
Undifferentiated is the most common subtype, accounting for > 60% of nasopharyngeal carcinoma
- It is also the most frequent pediatric subtype
Other subtypes in a descending order of frequency are keratinizing, nonkeratinizing differentiated and basaloid
Peak incidence in fourth to sixth decades; less than 20% occur in pediatric age group

Sites

As the name implies, nasopharyngeal carcinoma affects nasopharynx, with nasopharyngeal recess (i.e. fossa of Rosenmüller) as the most common affected site, followed by superior posterior wall
Extension to adjacent organs (e.g., nasal cavity, paranasal sinus, oropharynx, bone, orbit and infratemporal fossa) is common (Int J Radiat Oncol Biol Phys 2004;59:21)

Etiology

Strongly associated with Epstein-Barr virus (EBV) in endemic regions (Semin Diagn Pathol 2015;32:54, Mod Pathol 2017;30:S68)
Subset may be attributed to high risk human papillomavirus (HPV) in nonendemic and endemic regions (Head Neck 2014;36:511, Neoplasma 2016;63:107, Acta Virol 1988;32:261)
Other risk factors (Semin Diagn Pathol 2015;32:54):
- Genetic susceptibility; e.g., certain human leukocyte antigen (HLA) class I genotypes (Semin Diagn Pathol 2015;32:54)
- High levels of nitrosamines in preserved food (e.g., salted fish)
- Cigarette smoking
- Occupational exposure to chemical fumes, smoke, formaldehyde and wood dust
- Keratinizing subtype can arise as secondary malignancy years after radiation therapy for nonkeratinizing nasopharyngeal carcinoma (Hum Pathol 2000;31:227)

Diagrams / tables

Images hosted on other servers:

Age standardized incidence

Clinical features

Commonly presents with painless upper cervical lymphadenopathy secondary to lymph node metastasis or obstructive symptoms related to nasopharyngeal mass (e.g., postnasal drip, nasal discharge, epistaxis, serous otitis media and tinnitus) (Hong Kong Med J 1997;3:355)
Headache and symptoms of cranial nerve involvement in advanced disease with skull base involvement

Diagnosis

Biopsies are recommended if diagnosis is suspected (70% sensitive)

Laboratory

Positive Epstein-Barr virus (EBV) serology (Int J Cancer 2020;146:2923)
Elevated circulating EBV DNA or RNA; e.g., plasma or serum EBV encoded small RNA (EBERs)

Radiology description

MRI covering the nasopharynx and cervical regions is the preferred imaging modality to assess extent of disease and presence of intracranial extension (Radiopaedia: Nasopharyngeal Carcinoma [Accessed 5 April 2018])

Radiology images

Images hosted on other servers:

CT scan: wedge shaped mass

MRI: Enhanced mass in the fossa of Rosenmüller

Prognostic factors

5 year survival is ~ 65% for nonkeratinizing differentiated and undifferentiated subtypes
Keratinizing type has a poorer outcome, with frequent nodal metastasis and high mortality (Semin Diagn Pathol 2015;32:54)
Clinical stage is the most important prognostic factor: 5 year disease specific survival is 98% for stage I, 95% for stage II, 86% for stage III and 73% for stage IV
Other adverse prognostic factors include older age, male gender, large tumor volume and cranial nerve palsy

Case reports

49 year old woman with breast metastasis from nasopharyngeal carcinoma (Oncol Lett 2013;5:1859)
50 year old man with bilateral enlarging neck masses for 10 months (Case #100)
56 and 58 year old men with glandular differentiation in EBV positive nasopharyngeal carcinoma (Arch Pathol Lab Med 2000;124:1369)

Treatment

Radiation therapy is the mainstay of treatment for all histologic types of nasopharyngeal carcinoma (NCCN: NCCN Guidelines - Head and Neck Cancers [Accessed 14 October 2020])
Surgery is reserved for patients who fail to respond to radiation therapy

Gross description

Most specimens are endoscopic biopsy without specific gross findings
In resection specimens, the gross appearance is variable: smooth mucosal bulge, raised nodule with or without surface ulceration, infiltrative mass lesion or occult lesion identified only on microscopy

Microscopic (histologic) description

Nonkeratinizing, undifferentiated subtype
- Either syncytial arrangement of cohesive cells with indistinct cell margins (Regaud pattern) or diffuse cellular infiltrate of noncohesive cells (Schmincke pattern) resembling non-Hodgkin lymphoma (growth patterns have no clinical significance)
- Tumor cells have moderate eosinophilic to amphophilic cytoplasm, round nuclei, prominent eosinophilic nucleoli, vesicular chromatin
- No significant keratinization
- Apoptosis and brisk mitotic activity are invariably present
- Usually (but not always) prominent nonneoplastic lymphoplasmacytic infiltrate accompanying the tumor
- Necrosis is uncommon
Nonkeratinizing, differentiated subtype
- Usually interconnecting cords or trabeculae, with little or no keratinization; growth pattern is similar to urothelial carcinoma
- Tumor cells show well defined cell borders with variable intercellular bridges
- Background stroma demonstrates variable lymphoplasmacytic infiltrate
- Usually no desmoplastic response to invading tumor
- Subclassification of nonkeratinizing nasopharyngeal carcinoma into differentiated and undifferentiated subtypes is optional as it is not clinically or prognostically significant; if there is overlapping histology within the same tumor, classify according to the dominant component
Keratinizing subtype
- Indistinguishable from keratinizing squamous cell carcinoma of other body sites
- Obvious squamous differentiation as intercellular bridges and keratinization
- Can grade as well differentiated, moderately differentiated or poorly differentiated
- Desmoplastic response common
Basaloid subtype
- Indistinguishable from basaloid squamous cell carcinoma of other body sites
- Tumor cells have high nuclear / cytoplasmic ratio with scanty cytoplasm, giving the basaloid appearance
- Basaloid tumor nests and sheets, often with peripheral palisading and central comedo type necrosis

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D. and Songyang Yuan, M.D., Ph.D.

Nonkeratinizing, undifferentiated subtype

Nonkeratinizing undifferentiated subtype

AE1 / AE3+

EBV LMP1 IHC

Nonkeratinizing undifferentiated subtype

CK5 / 6+

EBER+

p63+

Nonkeratinizing, differentiated subtype

Nonkeratinizing differentiated subtype

Keratinizing subtype

Cytology description

Nonkeratinizing undifferentiated type shows clusters of tumor cells with indistinct cell border, vesicular nuclei and prominent central nucleoli
Background lymphocytes and plasma cells are commonly seen

Cytology images

Contributed by Marino E. Leon, M.D. and Case #100

FNA of a neck mass (Diff-Quik)

Pap stain

Cell block

Positive stains

EBV LMP is less specific and less widely used in North America but is used elsewhere
Pancytokeratin, high molecular weight CK, p63 and p40 are strongly positive
Rarely negative for high molecular weight CK and p40

Negative stains

CK7, CK20; rare cases may be positive for CK7
Other negative stains (may be useful to rule out mimics): CD45, S100, HMB45, MelanA, desmin, myoglobin, myogenin

Molecular / cytogenetics description

Detection of Epstein-Barr virus (EBV) by PCR or ISH (EBER) found in 75 - 100% of cases

Molecular / cytogenetics images

Contributed by Andrey Bychkov, M.D., Ph.D. and Bin Xu, M.D., Ph.D.

EBER ISH

Sample pathology report

Nasopharynx, biopsy:
- Nasopharyngeal carcinoma, nonkeratinizing, undifferentiated type (see comment)
- Comment: In situ hybridization for Epstein-Barr virus (EBER) is positive in this tumor.

Differential diagnosis

Diffuse large B cell lymphoma (DLBCL):
- Tumor cells of undifferentiated nasopharyngeal carcinoma have prominent central nuclei and indistinct cell borders in a background of reactive lymphoid infiltrate; hence, it may be mistaken for DLBCL, especially the immunoblastic type
- CD45+, CD20+, CK-, EBV-
Mucosal malignant melanoma:
- Primary mucosal melanoma of nasopharynx is exceedingly rare, with only a few case reports (J Cancer Res Ther 2014;10:416, J Craniofac Surg 2014;25:e567, J Contemp Brachytherapy 2013;5:157)
- Epithelioid and amelanotic melanoma may share some cytologic similarity; e.g. prominent nucleoli and syncytial sheet-like growth pattern
- Positive for S100, HMB45, MelanA, negative for CK and EBV
Oropharyngeal nonkeratinizing squamous cell carcinoma:
- Usually nonkeratinizing and shares certain histologic similarities
- Over 85% are p16+ and HPV+ but negative for EBV, compared with nasopharyngeal carcinomas that are commonly related to EBV
- In the rare incidence of HPV related nasopharyngeal carcinoma, radiologic correlation to determine the location of the primary tumor is needed
Rhabdomyosarcoma:
- Several subtypes of rhabdomyosarcoma, e.g., embryonal rhabdomyosarcoma (including the botryoid variant), alveolar rhabdomyosarcoma, spindle cell rhabdomyosarcoma and pleomorphic rhabdomyosarcoma, have been reported in sinonasal tract / nasopharynx
- Embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma can demonstrate a primitive small blue round cell morphology that could mimic undifferentiated nasopharyngeal carcinoma
- Positive for myogenic markers (desmin, myoglobin and myogenin), negative for CK and EBV
Sinonasal undifferentiated carcinoma:
- Arises in nasal cavity and paranasal sinuses only, hyperchromatic tumor cells with coarse chromatin, individual cell necrosis and necrosis of cell nests
- EBER- (Am J Surg Pathol 2002;26:371)

Additional references

El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017

Board review style question #1

A recent immigrant from Hong Kong presented with nasal discharge and a nasopharyngeal mass was biopsied. Which of the following statements is true?

In the United States, the lesion most commonly affects African Americans
Lesion commonly shows a squamous immunophenotype (i.e. positive for high molecular weight cytokeratin and p40)
Lesion is most commonly associated with high risk human papillomavirus (HPV)
Surgery is the standard treatment modality for this lesion

Board review style answer #1

B. Lesion commonly shows a squamous immunophenotype (i.e. positive for high molecular weight cytokeratin and p40)

Comment Here

Reference: Nasopharyngeal carcinoma

Board review style question #2

Which of the following statements about nasopharyngeal carcinoma is true?

B cell clonality may be demonstrated in the undifferentiated type of nonkeratinizing nasopharyngeal carcinoma
Most common subtype of nasopharyngeal carcinoma is the keratinizing type
Nasopharyngeal carcinoma may be related to EBV or HPV
Nasopharyngeal carcinoma predominantly affects patients from South America

Board review style answer #2

C. Nasopharyngeal carcinoma may be related to EBV or HPV

Comment Here

Reference: Nasopharyngeal carcinoma

Nonintestinal type

Table of Contents

Definition / general

Malignant tumor showing glandular differentiation, with presence of intraluminal mucin (in most cases)

Essential features

Gland forming malignancy of the sinonasal tract
Morphologically, lacks intestinal type features or characteristics of a salivary gland specific neoplasm
Histologically divided into 2 grades: low grade (LG) and high grade (HG)
Sinonasal renal cell-like adenocarcinoma (SRCLA) constitutes a definite subtype
~25% of LG sinonasal adenocarcinoma cases recur (Cancer 1982;50:312)
HG sinonasal adenocarcinoma fares worse with reports of occasional metastases

Terminology

Terminal tubulus adenocarcinoma
Tubulopapillary low grade adenocarcinoma
Low grade adenocarcinoma
Seromucinous adenocarcinoma

ICD coding

ICD-11
- 2C20.0 & XH74S1 - adenocarcinoma of nasal cavity & adenocarcinoma, NOS
- 2C22.0 & XH74S1 - adenocarcinoma of paranasal sinuses & adenocarcinoma, NOS

Epidemiology

LG sinonasal adenocarcinoma is uncommon and does not exhibit any sex predilection
HG sinonasal adenocarcinoma is rarer and affects men more frequently
Both LG and HG sinonasal adenocarcinoma occur over a wide age range, with a peak in the sixth decade

Sites

LG sinonasal adenocarcinoma arises most frequently in the middle turbinate (64%), followed by ethmoid sinus (20%) and other individual sinuses (Am J Surg Pathol 2009;33:401)
~50% of all HG sinonasal adenocarcinoma cases are locally advanced at presentation with involvement of multiple sites (Am J Surg Pathol 2011;35:971)

Pathophysiology

Exact pathogenesis of HG sinonasal adenocarcinoma is still unknown
Some LG sinonasal adenocarcinoma cases have been found to be enriched in ETV6::NTRK3 / ETV6::RET fusions and CTNNB1 mutations (Am J Surg Pathol 2017;41:1552, Case Rep Pathol 2018;2018:8741017)

Etiology

Exact etiology of LG sinonasal adenocarcinoma is yet to be unveiled
HG sinonasal adenocarcinoma may be related to exposure to carcinogens (such as wood dusts and other solvents) and occasionally also harbors association with high risk human papillomavirus (HPV) (Am J Surg Pathol 2011;35:971)

Clinical features

Nasal obstruction is most common presenting symptom
Patients harboring HG sinonasal adenocarcinoma additionally also present with epistaxis, pain, deformity and proptosis

Diagnosis

Imaging followed by biopsy

Radiology description

Nasopharyngeal endoscopy typically shows soft tissue mass
Bone destruction can be seen in HG sinonasal adenocarcinoma
Mucin producing adenocarcinoma shows hyperintensity on T2 weighted images and exhibits gradual enhancement on contrast enhanced T1 weighted images
Adenocarcinoma without mucin production shows isointensity to hypointensity on T2 weighted images (J Clin Med 2017;6:116)

Radiology images

Images hosted on other servers:

Heterogeneously hyperintense lesion on T2 weighted image

Prognostic factors

~25% of LG sinonasal adenocarcinoma cases recur; 6% of patients die due to tumor related morbidity (Cancer 1982;50:312)
Most patients of HG sinonasal adenocarcinoma die within 5 years, with evidence of local and distal metastasis
Few reported cases of SRCLA have recurred or have evidence of metastasis (Head Neck Pathol 2008;2:75)

Case reports

29 year old woman presented with a round polypoid mass at the posterior end of nasal septum (Ear Nose Throat J 2022 Aug 10 [Epub ahead of print])
35 year old African American man with von Hippel-Lindau (VHL) syndrome who developed SRCLA (Oral Oncol 2022;125:105705)
39 year old woman and 39 year old man with HG sinonasal adenocarcinoma exhibiting a distinct morphological and immunohistochemical phenotype and harboring ETV6::NTRK3 fusion (Virchows Arch 2023;483:187)
67 year old woman presented with a nasopharyngeal mass with an accompanying parapharyngeal mass (Curr Oncol 2017;24:e55)

Treatment

No standardized treatment algorithm; however, surgery followed by radiation is a mainstay in management
Tumor free resection margin is of utmost importance (World Neurosurg 2018;120:e962)

Clinical images

Images hosted on other servers:

Eustachian tube tumor

Gross description

Variable; however, usually appears as a red, polypoidal mass or firm, raspberry-like growth

Microscopic (histologic) description

LG sinonasal adenocarcinoma
- Papillary and glandular growth patterns (Cancer Manag Res 2021;13:1271)
  - Complex papillary structures with fibrovascular cores
  - Glandular (tubular) growth pattern has cribriform or back to back glands with little intervening stroma (Cancer 1982;50:312)
- Lining mucinous cuboidal to columnar epithelial cells have eosinophilic cytoplasm with uniform basally located rounded nuclei with finely granular chromatin
- Intraluminal mucin or material present
- Mitotic figures are rare
- Necrosis is absent
- Invasion into deeper soft tissue as well as into bone may be present
- Calcospherites and squamous morules may sometimes be seen (Case Rep Pathol 2018;2018:8741017)
HG sinonasal adenocarcinoma
- Exhibits more diversity in histomorphological patterns (Am J Surg Pathol 2011;35:971)
- Predominately solid or nested growth pattern
- Dispersed glandular structures or small cysts with papilla projecting into them
- Cells have intracytoplasmic mucin
- Destructive infiltrative growth pattern with invasion into bone
- Brisk mitotic activity with foci of necrosis
SRCLA
- Histological subtype reminiscent of renal cell carcinoma
- Tubulopapillary proliferation of tumor cells
- Predominately composed of polygonal cells, with clear or slightly eosinophilic cytoplasm (Head Neck Pathol 2008;2:75, Hum Pathol 2015;46:1598, Head Neck Pathol 2017;11:333)
- Tumor cells are glycogen rich, lacking mucin production
- Small, uniform, round nuclei with presence of intranuclear inclusions commonly
- Perineural or lymphovascular invasion, necrosis or severe pleomorphism are not seen

Microscopic (histologic) images

Contributed by Diana Bell, M.D. and Wai Szeto, M.D., M.S.

Low grade sinonasal adenocarcinoma

Tumor infiltrating
underlying stroma

Tubular growth pattern

High grade sinonasal adenocarcinoma

Nests of closely packed glands

Tumor necrosis

CK7

SOX10

Sinonasal renal cell-like adenocarcinoma

Tumor cells arranged as nests

Mimics renal cell carcinoma

Clear cytoplasm

CAIX

Positive stains

PAS (intracytoplasmic, diastase resistant granules), mucin stains, such as mucicarmine (intracellular or luminal)
Pancytokeratin (diffuse), CK7 (diffuse), p40 (focally, in few cases) (Virchows Arch 2003;443:152)
Subset of cases can also express DOG1, SOX10 and S100 protein (Head Neck Pathol 2015;9:436)
LG sinonasal adenocarcinoma: beta catenin (nuclear localization) (Case Rep Pathol 2018;2018:8741017)
HG sinonasal adenocarcinoma: focal expression of neuroendocrine antigens, such as synaptophysin, chromogranin, CD56 (Am J Surg Pathol 2011;35:971)
SRCLA: carbonic anhydrase IX (CAIX) and CD10 (diffuse) (Hum Pathol 2015;46:1598)

Negative stains

CDX2, SATB2, villin, MUC2, CK20 (infrequently positive)
HG sinonasal adenocarcinoma: beta catenin and mismatch repair (MMR) protein (wild type expression) (Mod Pathol 2005;18:315)
SRCLA: PAX8 or renal cell carcinoma (RCC) antibody

Molecular / cytogenetics description

No defined diagnostic molecular alterations to date
Some LG sinonasal adenocarcinoma cases have been found to be enriched in ETV6::NTRK3 / ETV6::RET fusions or CTNNB1 mutations (Am J Surg Pathol 2017;41:1552, Case Rep Pathol 2018;2018:8741017)
Occasional BRAF mutations (Pathol Oncol Res 2014;20:571)
No KRAS mutation
SRCLA: a couple of cases reported in patients with von Hippel-Lindau (VHL) syndrome (Oral Oncol 2022;125:105705)

Sample pathology report

Middle turbinate mass, biopsy:
- Invasive adenocarcinoma (low grade), nonintestinal type (see comment)
- Comment: The patient's clinical history of a mass in the middle turbinate is noted. Microscopic examination reveals complex, interwoven papillary architecture along with crowded back to back glands. The lining mucinous cuboidal to columnar epithelial cells have eosinophilic cytoplasm with uniform, basally located, rounded nuclei with finely granular chromatin. Occasional mitotic figures are present. Necrosis is absent. Lymphovascular or perineural invasion is not identified. On immunohistochemistry, the tumor cells are immunopositive for pancytokeratin and CK7 while negative for CK20, CDX2 and SATB2. The findings are consistent with low grade nonintestinal type sinonasal adenocarcinoma.

Differential diagnosis

Sinonasal intestinal type adenocarcinoma:
- Usually associated with wood dust exposure
- More papillary and less glandular
- Tall columnar and goblet cells
- Dirty background with hemorrhage and inflammation
- Mitotic activity
- Usually positive for CK20, CDX2, SATB2, villin and MUC2 (Ann Diagn Pathol 2006;10:215)
Metastatic papillary thyroid carcinoma:
- No surface epithelial dysplasia
- PAX8, TTF1 and thyroglobulin positive (Head Neck Pathol 2019;13:661)
Sinonasal papilloma, oncocytic type:
- Noninvasive papillary epithelial neoplasm
- Mixed exophytic and endophytic growth patterns
- Multiple layers of cuboidal to columnar cells
- Abundant oncocytic cytoplasm, scattered admixed ciliated or mucous columnar cells
- Intraepithelial neutrophilic inflammation, microcysts with mucin or neutrophilic microabscesses are characteristic
- No epithelial dysplasia
Respiratory epithelial adenomatoid hamartoma (REAH):
- Associated with allergy and inflammatory disorders
- Predilection for posterior nasal septum
- Lobular / polypoid growth pattern
- Proliferation of medium sized, elongated to rounded glands that expand from surface epithelium downward into the stroma
- Absence of complex glandular architecture, true invasion or dysplasia (Ear Nose Throat J 2021;100:495S)

Board review style question #1

The H&E images shown above depict a mass in the middle turbinate of a 45 year old man. Based on these images, what is the diagnosis?

Respiratory epithelial adenomatoid hamartoma (REAH)
Sinonasal nonintestinal type adenocarcinoma
Sinonasal papilloma, oncocytic type
Sinonasal renal cell-like adenocarcinoma

Board review style answer #1

B. Sinonasal nonintestinal type adenocarcinoma. The pictures show a tumor arranged as glands and interwoven papillae and infiltrating the underlying stroma. These features are consistent with a sinonasal nonintestinal type adenocarcinoma. Answers A and C are incorrect because these neoplasms lack true invasion into the underlying stroma. Answer D is incorrect because sinonasal renal cell-like adenocarcinoma is predominately composed of polygonal cells with clear cytoplasm, resembling a renal cell carcinoma.

Comment Here

Reference: Nonintestinal type sinonasal adenocarcinoma

Board review style question #2

Regarding sinonasal renal cell-like adenocarcinoma (SRCLA), which of the following statements is true?

Carbonic anhydrase IX (CAIX) and CD10 are diffusely immunopositive
PAX8 is immunopositive in this tumor
Renal cell carcinoma (RCC) marker is immunopositive
This tumor has high rate of metastasis

Board review style answer #2

A. Carbonic anhydrase IX (CAIX) and CD10 are diffusely immunopositive. Answers B and C are incorrect because unlike renal cell carcinomas, PAX8 (which is a transcription factor involved in development of the kidney) and RCC immunomarkers are immunonegative in SRCLA. Answer D is incorrect because no reported cases have metastases to date.

Comment Here

Reference: Nonintestinal type sinonasal adenocarcinoma

NUT carcinoma

Table of Contents

Definition / general

Aggressive carcinoma defined by translocations involving the NUT gene and frequent squamous differentiation

Essential features

Highly aggressive malignancy with median survival of < 1 year
Histologically defined by primitive round cells with areas of abrupt keratinization
Caused by translocations involving the NUT gene (15q14), most commonly with BRD4 (19p13)
Speckled nuclear positivity for NUT1 immunohistochemistry is sensitive and specific for diagnosis

Terminology

NUT stands for nuclear protein in testis
Formerly called NUT midline carcinoma due to proclivity for midline sites

Epidemiology

Although originally described in children, affects people of all ages (Head Neck Pathol 2013;7:11)
No sex or geographic predilection (Head Neck Pathol 2013;7:11)
No clear risk factors established to date (Head Neck Pathol 2013;7:11)

Clinical features

Aggressive malignancy with median survival of < 1 year (Head Neck Pathol 2013;7:11)
~35% involve the head and neck, most commonly in the sinonasal tract (Head Neck Pathol 2013;7:11)
Although also common in other midline sites such as the mediastinum, can occur anywhere in the body (Head Neck Pathol 2013;7:11)

Radiology images

Images hosted on other servers:

Large nasal mass

Case reports

14 year old girl with ethmoid sinus mass (Oncogenesis 2015;4:e174)
18 year old woman with undifferentiated sinonasal mass (Pathol Res Pract 2014;210:383)
48 year old man with vision changes (Saudi J Ophthalmol 2018;32:62)
53 year old man with nasal cavity mass (Head Neck Pathol 2017;11:389)
54 year old woman with nasal mass (Arch Pathol Lab Med 2011;135:1494)

Treatment

Tumors generally show minimal response to radiation and conventional chemotherapy (Head Neck Pathol 2013;7:11)
In clinical trials, some patients show rapid response to extraterminal bromodomain inhibitors although prognosis remains poor (Cancer Discov 2016;6:492)

Clinical images

Images hosted on other servers:

Lacrimal mass

Nasopharyngeal endoscopy

Gross description

Highly infiltrative tumor frequently involving multiple anatomic subsites
Nonspecific white-tan cut surface commonly demonstrating prominent necrosis

Microscopic (histologic) description

Primitive small to medium sized cells with minimal indistinct to clear cytoplasm
Monotonous round to oval nuclei with variably prominent nucleoli
High mitotic rate with prominent tumor necrosis
Foci of abrupt squamous differentiation with clear to eosinophilic cytoplasm and keratin pearl formation
Areas of spindled cells frequently present
Dense neutrophil infiltrate seen in subset of cases

Microscopic (histologic) images

Contributed by Lisa Rooper, M.D.

Primitive small to medium cells

Highly infiltrative growth

Monotonous nuclei

Prominent necrosis

Abrupt keratinization

Prominent spindled foci

Infiltrating neutrophils

NUT1

Contributed by Brendan Dickson, M.D.

Abrupt keratinization

Necrosis

Undifferentiated areas

p63

NUT1

AE1 / 3

Cytology images

Images hosted on other servers:

Aspirate of metastasis

Positive stains

NUT1 diffuse speckled nuclear positivity is 87% sensitive and 100% specific (Am J Surg Pathol 2009;33:984)
Pancytokeratin, EMA consistently positive (Am J Surg Pathol 2012;36:1216)
p63 / p40 ~67% (Am J Surg Pathol 2012;36:1216)
CD34 ~30 - 50% (Am J Surg Pathol 2012;36:1216)
INI1 retained (Surg Pathol Clin 2017;10:103)

Negative stains

CD99, NKX2.2
S100, synaptophysin, chromogranin focal expression in rare cases (Am J Surg Pathol 2012;36:1216)

Electron microscopy description

Large, irregular nuclei with prominent compact nucleoli (Ultrastruct Pathol 2012;36:280)
Abundant cytoplasm with prominent tonofilament bundles, scattered pleomorphic granules and numerous desmosomal junctions (Ultrastruct Pathol 2012;36:280)

Molecular / cytogenetics description

Defined by translocations involving the NUT gene on 15q14 (Cancer Discov 2014;4:928)
BRD4-NUT (19p13) fusion is present in 67% of cases (Cancer Res 2003;63:304)
Other cases show BRD3-NUT or NSD3-NUT fusions (Oncogene 2008;27:2237, Cancer Discov 2014;4:928)
Fusions block epithelial differentiation and maintain proliferation in tumor cells (Oncogene 2008;27:2237)
In situ hybridization for high risk HPV and EBV is uniformly negative (Int J Surg Pathol 2013;21:102)

Sample pathology report

NUT carcinoma; see note:
- Note: Immunostains show that the tumor cells are positive for AE1 / AE3, p40 and NUT1 and negative for CD99 and synaptophysin, supporting the above diagnosis. NUT carcinoma is a rare, highly aggressive malignancy that is defined by translocations involving the NUT gene. Please see www.nmcregistry.org for information about enrolling the patient into the International NUT Carcinoma Registry and opportunities for clinical trials.

Differential diagnosis

Basaloid squamous cell carcinoma: can also show abrupt keratinization and p63 / p40 positivity; negative for NUT1
Sinonasal undifferentiated carcinoma: also high grade tumor; has more cytologic atypia, lacks keratinization, negative for NUT1 and p63 / p40, frequent IDH2 mutations
High grade neuroendocrine carcinoma: also high grade tumor; lacks keratinization, negative for NUT1 and p63 / p40 and positive for synaptophysin, chromogranin and INSM1
Adamantinoma-like Ewing sarcoma: can also show abrupt keratinization and p63 / p40 positivity; negative for NUT1 and positive for CD99 and NKX2.1
SMARCB1 deficient sinonasal carcinoma: also high grade tumor that can be positive for p63 / p40; lacks keratinization, negative for NUT1 and shows loss of INI1

Board review style question #1

An 18 year old woman presented with a destructive sinonasal tumor; biopsy findings are shown below. What immunohistochemical finding would you expect?

Cytoplasmic positivity for cytokeratin without significant reactivity for any other markers
Diffuse strong positivity for synaptophysin and INSM1
Loss of nuclear INI1 expression
Speckled nuclear positivity for NUT1

Board review style answer #1

D. Speckled nuclear positivity for NUT1. The picture depicts a NUT carcinoma, diagnosis of which is suggested by the presence of monotonous primitive cells interspersed with areas of abrupt keratinization. The correct immunohistochemical finding for this tumor is speckled nuclear positivity for NUT1, a sensitive and specific marker of this tumor type. The other immunoprofiles listed would be more characteristic of tumors that lack the characteristic keratinization pattern depicted in this photomicrograph, including sinonasal undifferentiated carcinoma (A. Cytoplasmic positivity for cytokeratin without significant reactivity for any other markers), small cell carcinoma (B. Diffuse strong positivity for synaptophysin and INSM1) and SMARCB1 deficient sinonasal carcinoma (C. Loss of nuclear INI1 expression).

Comment Here

Reference: NUT carcinoma

Board review style question #2

What is the most common genetic abnormality identified in NUT carcinoma?

BRD3-NUT
BRD4-NUT
Deletion of NUT
NSD3-NUT

Board review style answer #2

B. BRD4-NUT. The most common genetic abnormality identified in NUT carcinoma is BRD4-NUT fusion, which is present in ~67% of cases. The other translocations listed, BRD3-NUT and NSD3-NUT, are less common variant fusions seen in NUT carcinoma; deletion of NUT has not been reported as a cause of this tumor type.

Comment Here

Reference: NUT carcinoma

Olfactory neuroblastoma

Table of Contents

Definition / general

Malignant neuroectodermal tumor commonly located at superior aspect of nasal cavity showing neuroblastic differentiation (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
Thought to arise from olfactory membrane or olfactory placode (plate-like thickening of embryonic ectoderm from which a nerve ganglion or sensory organ will develop) which extends from roof of nasal cavity in fetus to midnasal septum and superior turbinate
Not related to neuroblastoma elsewhere in body

Essential features

Originated and centered around cribriform plate of nasal cavity
Small blue round cell tumor with lobulated growth pattern and abundant neuropil
Homer Wright pseudorosettes and Flexner-Wintersteiner rosettes may be seen
The most important prognostic factors are Hyams grade and Kadish stage

Terminology

Also called esthesioneuroblastoma, esthesioneuroepithelioma or olfactory placode tumor

ICD coding

ICD-O: 9522/3 - Olfactory neuroblastoma
ICD-10: C30.0 - Malignant neoplasm of nasal cavity and middle ear

Epidemiology

Patients of all ages, 2 to 90 years
No obvious gender, ethnic or familial predilection
Annual incidence of 0.4 per million (Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252)
2% of all sinonasal neoplasms

Sites

Usually confined to the cribriform plate and upper nasal vault; rarely in nasopharynx, maxillary or ethmoid sinus (Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252)
May become locally invasive into paranasal sinuses, nasopharynx, palate, orbit, skull base, brain

Pathophysiology

Theorized to originate from specialized sensory neuroepithelium located in superior nasal cavity, including cribriform plate of ethmoid, nasal roof, superior nasal concha and superior nasal septum (Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252)

Etiology

None identified

Clinical features

Usually presents with nonspecific syndromes of nasal obstruction, epistaxis, headache and rhinorrhea (Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252)
Rare symptoms include anosmia, visual disturbance, paraneoplastic syndromes (e.g. syndrome of inappropriate antidiuretic hormone secretion (SIADH))

Radiology description

Typical finding is a dumbbell shaped mass centered at cribriform plate

Radiology images

Images hosted on other servers:

Tumor extending into cribriform plate and lateral lamella

Large, avidly enhancing skull base mass in left nasal cavity

Olfactory neuroblastoma, a. coronal view, b sagittal view

Prognostic factors

20% develop regional or distant metastases, usually to cervical lymph nodes and lung; late recurrence (after 10 years) is common
Grade and stage are the most important prognostic factors
Hyams histologic grade (Table 1) is the most widely used grading system which encompasses six histologic features and is an independent prognostic factor (Head Neck Pathol 2015;9:51, Hyams VJ. Olfactory neuroblastoma (Case 6) In: Batsakis JG, Hyams VJ, Morales AR, editors, Special tumors of the head and neck, Chicago: ASCP Press; 1982. pp. 24-29)
Kadish staging system (Cancer 1976;37:1571, Head Neck 2017;39:1962, Head Neck Pathol 2015;9:51) and Morita modification (Table 2) (Head Neck Pathol 2015;9:51, Neurosurgery 1993;32:706) are the staging systems that are most commonly used: the 5 year survival for stages A, B and C are 75%, 68% and 41%, respectively (Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252)

Diagrams / tables

Table 1: Hyams grade for olfactory neuroblastoma

	Grade I	Grade II	Grade III	Grade IV
Architecture	Lobular	Lobular	Variable	Variable
Fibrillary matrix	Prominent	Present	Minimal	Absent
Mitosis	Absent	Present	Prominent	Marked
Necrosis	Absent	Absent	May present	Common
Nuclear pleomorphism	Absent	Moderate	Prominent	Marked
Rosettes	Homer Wright	Homer Wright	Flexner- Wintersteiner	Flexner- Wintersteiner

Table 2: Staging systems of olfactory neuroblastoma

Kadish staging:

Confined to nasal cavity
Involves nasal cavity and paranasal sinuses
Extends beyond the nasal cavity and paranasal sinuses

Morita modification:

Confined to nasal cavity
Involves nasal cavity and paranasal sinuses
Extends beyond the nasal cavity and paranasal sinuses
Regional or distant metastasis

Case reports

30 year old woman and 67 year old woman with varied atypical clinical presentation (J Clin Diagn Res 2016;10:PD01)
35 year old man with divergent differentiation (Head Neck Pathol 2017;11:531)
41 year old man with multifocal ectopic olfactory neuroblastoma (Am J Case Rep 2016;17:268)
43 year old woman with a mass in the right nasal cavity (Head Neck Pathol 2016;10:256)
44 year old man with aberrant pattern of cytokeratin expression (Head Neck Pathol 2017;11:262 )

Treatment

Complete surgical excision (may require craniofacial resection), with radiation therapy or chemotherapy

Clinical images

Images hosted on other servers:

Nasal endoscopy

Bifrontal craniotomy

Gross description

Red-gray, highly vascular, polypoid mass

Microscopic (histologic) description

Low grade olfactory neuroblastoma usually contains nests and lobules of monotonous tumor cells with round nuclei, indistinct nucleoli and scanty cytoplasm in association with a vascular-rich to hyalinized stroma; fibrillary neural matrix may be present
High grade tumors may show solid growth, marked mitotic activity, nuclear pleomorphism, necrosis and no neuropil
Homer Wright pseudorosettes: neoplastic cells palisading around a central zone of fibrillar neural matrix; their presence in a nasal tumor is characteristic for olfactory neuroblastoma
Flexner-Wintersteiner rosettes: palisading tumor cells surrounding a true central lumen
Perivascular pseudorosettes may be present but are non-specific
Other findings: melanin pigment, neurons, divergent differentiation (e.g. rhabdomyoblastic, glandular and squamous differentiation)

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Lobulated growth,
microcalcification,
abundant fibrillar
neural matrix

Lobulated growth with
infiltration between
submucosal glands

Hyams grade I
olfactory
neuroblastoma

Flexner-Wintersteiner
rosettes

Homer Wright
pseudorosettes

Synaptophysin
diffusely positive
in tumor cells

S100 highlights
sustentacular cells

Positive stains

Synaptophysin, chromogranin, CD56, neurofilament, S100 in sustentacular cells at periphery of cell nests
Keratins, e.g. cytokeratin AE1/AE3, CAM5.2 and CK18, are commonly negative, but up to a third may show focal positivity
INI1
Area of rhabdomyoblastic differentiation if present is positive for desmin and myogenin
Calretinin (Am J Surg Pathol 2011;35:1786)

Negative stains

CD99, FLI1, EMA, p40, EBER, NUT, lymphoid markers (e.g. CD45)
With the exception of olfactory neuroblastoma with rhabdomyoblastic differentiation, the tumor is negative for desmin and myogenin

Electron microscopy description

Dense core neurosecretory granules, microtubules, neuritic processes, neurofilaments (Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252)

Molecular / cytogenetics description

Recent next generation sequencing studies have shown that olfactory neuroblastoma has high level but heterogenous chromosomal instability and copy number alterations (Oncotarget 2016;7:52584)
Absence of characteristic fusions of other small blue round cell tumors that may occur in the sinonasal tract, e.g. Ewing sarcoma EWSR1 fusion and alveolar rhabdomyosarcoma PAX3 or PAX7 fusion

Sample pathology report

Nasal cavity, left; biopsy:
- Olfactory neuroblastoma, Hyams grade II (see comment)
- Comment: Immunohistochemistry studies show that the tumor is positive for synaptophysin and chromogranin, whereas negative for cytokeratin. S100 highlighted the sustentacular network. The overall immunoprofile supports the diagnosis.

Differential diagnosis

Surg Pathol Clin 2017;10:103

Lymphoma: positive for CD45 and other lymphoid markers
Melanoma: positive for S100, SOX10, MelanA, HMB45
Small round cell sarcoma:
- Ewing sarcoma: positive for CD99, FLI1, t(11,22) / FLI1::EWSR1 fusion
- Embryonal rhabdomyosarcoma: diffusely positive for desmin and myogenin
- Alveolar rhabdomyosarcoma: diffusely positive for desmin and myogenin, PAX3 or PAX7 fusion
- Mesenchymal chondrosarcoma: NCOA2 fusion
Carcinoma:
- Small cell carcinoma / poorly differentiated neuroendocrine carcinoma: diffusely positive for cytokeratin, negative for neurofilament and S100
- Sinonasal undifferentiated carcinoma: negative for synaptophysin and chromogranin
- NUT midline carcinoma: positive for NUT
- Adenoid cystic carcinoma: negative for synaptophysin and chromogranin; positive for myoepithelial markers calponin, SMA and S100 and MYB::NFIB fusion
- SMARCB1-deficient sinonasal carcinoma: loss of INI1

Board review style question #1

The tumor most commonly locates to the lower portion of nasal cavity
Tumor necrosis, nuclear pleomorphism and high mitotic index are part of the staging system
The tumor is not associated with similar appearing tumors elsewhere in the body
SMARCB1 (INI1) immunohistochemistry is lost in this tumor

Board review style answer #1

C. Olfactory neuroblastoma is not associated with neuroblastoma elsewhere in the body

Comment Here

Reference: Olfactory neuroblastoma

Board review style question #2

The most important prognostic factor is N-MYC amplification
It is most commonly originated from the medial wall of maxillary sinus
Most tumors are diffusely positive for CAM5.2
It may contain areas with rhabdomyoblastic differentiation

Board review style answer #2

D. It may contain areas with rhabdomyoblastic differentiation

Comment Here

Reference: Olfactory neuroblastoma

Respiratory epithelial adenomatoid hamartoma

Table of Contents

Definition / general

Acquired overgrowth of surface glands characterized by pseudostratified epithelium with cilia surrounded by a thickened basement membrane
Currently classified as nonneoplastic hamartoma in the WHO classification 5th edition (Head Neck Pathol 2022;16:1)
Chondro-osseous respiratory epithelial (CORE) hamartoma is considered a subtype of respiratory epithelial adenomatoid hamartoma (REAH) (Head Neck Pathol 2022;16:1)

Essential features

Overgrowth of medium sized glands displacing normal elements (such as seromucinous glands)
Lining of glands is pseudostratified respiratory epithelium with cilia
Glands are surrounded by thickened basement membrane

Terminology

Glandular hamartoma (not recommended)
Subtype: chondro-osseous and respiratory epithelial hamartoma

ICD coding

ICD-10: Q85.9 - phakomatosis, unspecified

Epidemiology

M:F = 3:1 to 7:1 (Ann Otol Rhinol Laryngol 1995;104:639, Am J Rhinol Allergy 2013;27:322)
Median age: 58 years (range: 27 - 81 years) (Ann Otol Rhinol Laryngol 1995;104:639, Am J Rhinol Allergy 2013;27:322)

Sites

Most commonly occurs in the posterior septum of nasal cavity, particularly the olfactory cleft (Ann Otol Rhinol Laryngol 1995;104:639, Am J Rhinol Allergy 2013;27:322)
Other sites of involvement include lateral wall of nasal cavity, middle meatus, nasal turbinate, nasopharynx, paranasal sinuses (ethmoid, maxillary or frontal) (Laryngoscope Investig Otolaryngol 2022;7:1292, Ann Otol Rhinol Laryngol 1995;104:639, Am J Rhinol Allergy 2013;27:322)

Etiology

> 66% are associated with atopic disease or chronic rhinosinusitis (Am J Rhinol Allergy 2020;34:610, Am J Rhinol Allergy 2013;27:322)

Clinical features

Patients commonly present with nonspecific symptoms (e.g., nasal congestion / obstruction, headache, rhinorrhea and epistaxis)
Often has a longstanding history of chronic rhinosinusitis (Ann Otol Rhinol Laryngol 1995;104:639)
May be unilateral or bilateral (Ann Otol Rhinol Laryngol 1995;104:639, AJNR Am J Neuroradiol 2013;34:1086)

Diagnosis

Identifying diagnostic histologic features in an endoscopic resection specimen is necessary for the diagnosis

Radiology description

Expansion of the maximum olfactory cleft width (especially when > 10 mm) is a common finding on computed tomography (CT) (Am J Rhinol Allergy 2013;27:322, AJNR Am J Neuroradiol 2013;34:1086)
No evidence of destructive growth or bone invasion

Radiology images

Images hosted on other servers:

Widened olfactory cleft

Prognostic factors

Benign lesion: negligible risk of recurrence if resected completely (Am J Rhinol Allergy 2013;27:322)
Local recurrence is rare

Case reports

17 year old boy with respiratory epithelial adenomatoid hamartoma (Ear Nose Throat J 2022 May 9 [Epub ahead of print])
62 year old man with respiratory epithelial adenomatoid hamartoma of the maxillary sinus (Acta Otorhinolaryngol Ital 2006;26:225)
75 year old man with bilateral nasal mass (Proc (Bayl Univ Med Cent) 2017;30:221)
83 year old woman with chondro-osseous respiratory epithelial adenomatoid hamartoma (Case Rep Otolaryngol 2019;2019:5247091)

Treatment

Complete excision, often through the endoscopic approach, is considered curative

Gross description

Polypoid or exophytic, rubbery, tan-brown, with a firm to gritty consistency

Gross images

Images hosted on other servers:

Polypoid glistening mass

Microscopic (histologic) description

Respiratory epithelial adenomatoid hamartoma (REAH)
- Proliferation (often polypoid) of medium sized glands lined by ciliated epithelium
- Glands are surrounded by thick eosinophilic basement membranes
- Lesion replaces background normal elements, often resulting in a decreased number of seromucinous glands
- Features of chronic rhinosinusitis (chronic inflammation) and inflammatory sinonasal polyp (edematous stroma admixed with chronic inflammation) may be seen in the background
Chondro-osseous respiratory epithelial (CORE) hamartoma subtype (Int Arch Otorhinolaryngol 2013;17:218, Int J Surg Pathol 2022;30:448)
- CORE hamartoma is composed of 2 components, often intimately intermixed with each other
  - Glandular component composed of glands lined by respiratory type epithelium with cilia; the extent of glandular component is often less prominent compared with REAH
  - Mesenchymal component that ranges from immature mesenchyme, cartilage, bone trabeculae or chondromyxoid matrix

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Respiratory epithelial adenomatoid hamartoma (REAH)

Proliferation of medium sized glands

Thickened basement membrane

Glands with cilia

Scattered seromucinous glands

Chondro-osseous respiratory epithelial (CORE) hamartoma

Glands and chondromyxoid stroma

Myxoid mesenchyme and gland

Epithelium with cilia

Positive stains

Diagnosis is typically rendered based on H&E alone; immunohistochemistry is not required for this entity
CK7 (Head Neck Pathol 2008;2:203)

Negative stains

CK20 and CDX2 (Head Neck Pathol 2008;2:203)

Molecular / cytogenetics description

Currently considered as a nonneoplastic hamartoma in the WHO classification 5th edition; however, increased fractional allelic loss is detected, suggesting a possible neoplastic nature (Am J Surg Pathol 2006;30:1576)

Sample pathology report

Left nasal cavity, excision:
- Respiratory epithelial adenomatoid hamartoma

Differential diagnosis

Inflammatory sinonasal polyp:
- May have occasional invagination of surface epithelium but lacks proliferation of glandular component and the thickened surrounding basement membrane

Sinonasal papilloma, inverted type:

	Respiratory epithelial adenomatoid hamartoma	Sinonasal papilloma, inverted type
Location	Commonly on the posterior septum close to the olfactory cleft	Typically on the lateral nasal wall
High risk HPV	Negative	May be positive
Thickened basement membrane	Present	Absent
Epithelial lining	Respiratory type epithelium of normal thickness with cilia	Hyperplastic (thickened) squamous, transitional or respiratory type epithelium
Transmigrating neutrophils / neutrophilic microabscesses	Absent	Present

Sinonasal adenocarcinoma, nonintestinal type:
- Complex architecture manifested as densely packed back to back tubular glands or fused / cribriform glandular architecture
- Lacks cilia and thickened basement membrane
- May show other malignant features (e.g., nuclear pleomorphism, prominent mitotic activity, necrosis, perineural invasion and lymphovascular invasion)
- May harbor diagnostic mutations or fusions involving NTRK3, MET, NRG1, PRKACA, AKT1, BRAF and CTNNB1 genes (Mod Pathol 2022;35:1160)
Biphenotypic sinonasal sarcoma:
- Surface / glandular epithelium overlying biphenotypic sinonasal sarcoma may show changes resembling REAH
- REAH lacks S100+ / desmin+ hypercellular spindle cell proliferation in between glands

Board review style question #1

An excision of a nasal polyp from 50 year old man shows the histology pictured above. What is the diagnosis?

Inflammatory sinonasal polyp
Respiratory epithelial adenomatoid hamartoma (REAH)
Sinonasal adenocarcinoma, nonintestinal subtype
Sinonasal papilloma, inverted subtype

Board review style answer #1

B. Respiratory epithelial adenomatoid hamartoma (REAH). The H&E shows typical histologic findings of respiratory epithelial adenomatoid hamartoma, characterized by proliferation of medium sized glands with cilia surrounded by thickened basement membrane. See Differential diagnosis section for features to distinguish REAH from its diagnostic mimickers, such as inverted papilloma, inflammatory polyp and nonintestinal sinonasal adenocarcinoma.

Comment Here

Reference: Respiratory epithelial adenomatoid hamartoma

Board review style question #2

Which of the following statements about respiratory epithelial adenomatoid hamartoma (REAH) is true?

30% of REAH is associated with high risk human papillomavirus
Classified as a benign neoplasm in the WHO classification
Commonly located on the nasal septum rather than lateral nasal wall
Has ~15% risk of recurrence and a small risk of distant metastasis

Board review style answer #2

C. Commonly located on the nasal septum rather than lateral nasal wall. Answer A is incorrect because REAH is not associated with high risk human papillomavirus. Answer B is incorrect because REAH is classified as a nonneoplastic lesion in WHO classification. Answer D is incorrect because REAH has a very low (if any) risk of recurrence if completely excised and no distant metastasis has been reported.

Comment Here

Reference: Respiratory epithelial adenomatoid hamartoma

Rhinosclerosis

Table of Contents

Definition / general

Rare; chronic granulomatous disease of nasal cavity (95 - 100%), nasopharynx (18 - 43%), larynx (15 - 40%), trachea (12%) or bronchi (2 - 7%) caused by Klebsiella rhinoscleromatis
Usually low socioeconomic environments of central / South America, Africa, Middle East, Philippines and India; rare in US (usually immigrants)
Most common in young adults
Slowly progressive with remission and relapse; not fatal unless it obstructs the airway
Microbiology: MacConkey agar cultures are 50 - 60% sensitive; bacteria is gram negative, encapsulated, nonmotile, diplobacillus, member of Enterobacteriaceae, not normal flora, infective via drops or contamination of material that is inhaled

Treatment

Antibiotics for months to years
Possibly steroids, surgery to treat airway compromise and tissue deformity

Case reports

32 year old woman with supraglottic granulomas (Arch Pathol Lab Med 2001;125:159)

Microscopic (histologic) description

Catarrhal / atrophic, granulomatous and sclerotic stages
Initially: squamous metaplasia and inflamed granulation tissue
Later: pseudoepitheliomatous squamous hyperplasia with foamy macrophages (Mikulicz cells containing bacteria), plasma cells with Russell bodies and granulomatous inflammation
Late: fibrosis, lymphocytes and plasma cells but no Mikulicz cells

Positive stains

PAS, Giemsa, Steiner or Hotchkiss-McManus stains for gram negative bacteria

Electron microscopy description

Large phagosomes containing bacilli and finely granular material (antibodies on bacterial surface and aggregates of bacterial mucopolysaccharides)

Differential diagnosis

Leprosy
Other granulomatous processes
Rosai-Dorfman disease

Rhinosporidiosis

Table of Contents

Definition / general

Caused by Rhinosporidium seeberi, traditionally thought to be a fungus but actually an aquatic protistan parasite (J Clin Microbiol 1999;37:2750)
Endemic in southern India, Sri Lanka and emigrants from this region (Diagn Pathol 2006;1:25, Singapore Med J 2004;45:224); rare indigenous cases in U.S. (South Med J 1996;89:65)
Natural aquatic habitat, transmitted through traumatized epithelium, most commonly in nose and eye, also skin, ear, genitals and rectum

Risk factors

Bathing or working in stagnant water
Rarely presents with disseminated skin disease (Indian J Dermatol Venereol Leprol 2007;73:185, Indian J Dermatol Venereol Leprol 2001;67:332)
Not transmitted person to person

Case reports

29 year old man from India with progressively increasing nasal obstruction (Case of the Week #97)

Treatment

Surgical excision, may recur
No effective medical treatment

Gross description

Hyperplastic, polypoid, red, granular masses of nasal cavity
Yellow pinhead spots represent mature sporangia
Superficial mucus is common

Microscopic (histologic) description

Large (100 - 450 microns), thick walled sporangia with 1000+ endospores, each 6 - 10 microns, accompanied by a mixed inflammatory infiltrate
May not be present in all sections and may need additional sampling for diagnosis

Microscopic (histologic) images

Contributed by Hanni Gulwani, M.B.B.S. (Case #97), Veena Maheshwari, M.D., Kiran Alam, M.D., Anshu Jain, M.D., Alia Albawardi, M.B.B.S. and @DrTravisBrown on Twitter

Various images

28 year old from Nepal with uvular mass; left to right: H&E (4 images), GMS, PAS

Rhinosporidiosis

Positive stains

GMS, PAS

Differential diagnosis

Coccidiodes immitis: smaller spherules (30 - 60 microns), smaller endospores (2 - 5 microns)
Myospherulosis: large tissue spaces with saclike structures containing brown spherules that resemble Prototheca but are actually clumped red blood cells, GMS-
Often arthroconidia and hyphae

Salivary gland anlage tumor

Table of Contents

Definition / general

Extremely rare, benign, congenital, biphasic tumor with mixed epithelial and myoepithelial elements of midline nasopharynx

Essential features

Presents within first 6 weeks of life with a midline nasopharyngeal mass and symptoms related to airway / nasal obstruction (Pediatrics 2003;112:e66)
Covered by nonkeratinizing squamous epithelium
Peripheral squamous nests and duct-like structures
Central stromal nodules consisting of uniform ovoid to spindled cells (Am J Surg Pathol 1994;18:25)
Good prognosis; excision is curative (Int J Pediatr Otorhinolaryngol 2005;69:149)

Terminology

Salivary gland anlage tumor (SGAT)
Congenital pleomorphic adenoma

ICD coding

ICD-10: D49.0 - neoplasm of unspecified behavior of digestive system

Epidemiology

Extremely rare
Presents in immediate neonatal period or in early infancy (by age of 6 weeks)
Male predilection (Int J Pediatr Otorhinolaryngol 2005;69:149)

Sites

Located or near midline in the nasopharynx or posterior nasal septum

Pathophysiology

Congenital / developmental anomaly, likely represents hamartoma of minor salivary gland origin

Clinical features

Obstructive symptoms manifesting as respiratory distress, feeding difficulties or nasal airway obstruction

Diagnosis

CT or MRI of the nasal sinuses
Diagnosis is by endoscopic biopsy / debulking or surgical resection

Radiology description

Lobular, midline soft tissue mass in the naso-oropharynx without infiltration into surrounding structures
T1 isointense, T2 hyperintense, homogeneously enhancing mass measuring 1 to 2 cm on MRI (Pediatr Radiol 2015;45:453, AJNR Am J Neuroradiol 2009;30:1022)

Radiology images

Contributed by Scott Poswilko, M.D.

Naso-oropharyngeal mass (T1 axial)

Naso-oropharyngeal mass (T1 coronal)

Naso-oropharyngeal mass (T2 axial)

Prognostic factors

Excellent prognosis
Curable by surgical resection

Case reports

Newborn boy and 6 week old girl with nasopharyngeal mass (Fetal Pediatr Pathol 2011;30:116)
Newborn boy with life threatening nasal obstruction (Pediatrics 2003;112:e66)
Newborn boy with acute airway obstruction secondary to nasopharyngeal mass (Int J Pediatr Otorhinolaryngol 2005;69:149)
2 week old infant with difficulty breathing since birth (AJNR Am J Neuroradiol 2009;30:1022)
Congenital salivary gland anlage tumor causing severe neonatal respiratory distress (Fetal Pediatr Pathol 2010;29:323)
Salivary gland anlage tumor with widespread necrosis and large cyst formation (Pathology 1996;28:128)

Treatment

Simple surgical excision

Gross description

Polypoid, gray, rubbery, grossly encapsulated tissue fragment with homogenous cut surface without necrosis or hemorrhage

Gross images

Images hosted on other servers:

Lobulated mass

Microscopic (histologic) description

Surface covered by nonkeratinizing squamous mucosa
Multiple submucosal, cellular, solid stromal nodules separated by hypocellular stroma in the center
Duct-like epithelial structures and squamous nests with variable keratinization more prominent toward periphery of stromal nodules (Int J Pediatr Otorhinolaryngol 2005;69:149)
Internodular epithelial components blend into cellular nodules
Cellular stromal nodules composed of mesenchymal appearing, fusiform to spindled to ovoid cells forming short fascicles or trabeculae (Pediatr Pathol Lab Med 1996;16:973)
Stromal cells are uniform and show bland cytology with dispersed chromatin, scant eosinophilic cytoplasm and indistinct cell borders (Fetal Pediatr Pathol 2011;30:116)
Background hypocellular collagenous stroma with focal chondromyxoid areas
Mitotic figures and hemorrhagic necrosis may be present

Microscopic (histologic) images

Contributed by Josephine K. Dermawan, M.D., Ph.D. and Laura O. Rabinowitz, M.D.

Submucosal lobular proliferation

Nonkeratinizing squamous mucosa

Epithelial and mesenchymal components

Duct-like structures and calcifications

Focal chondromyxoid stroma

Ovoid to spindled stromal cells

Positive CK7

Positive p63

Variable SMMS1

Focal S100

Positive stains

Epithelial components:
- Cytokeratins (pancytokeratins, CK7)
- p63
Mesenchymal components:
- Variable for cytokeratins (pancytokeratins, CK7)
- Alpha smooth muscle actin, muscle specific actin, smooth muscle myosin
- May have focal S100 (Pediatr Pathol Lab Med 1996;16:973, Am J Surg Pathol 1994;18:25)

Electron microscopy description

Stromal-like cells have ultrastructural features of myoepithelial cells (Am J Surg Pathol 1994;18:25)

Sample pathology report

Soft tissue mass, nasopharynx, excision:
- Salivary gland anlage tumor (see comment)
- Comment: Histologic sections demonstrate a lobulated nasopharyngeal proliferation which shows mixed epithelial and myoepithelial components. The tumor shows tubules and ducts with variable keratinization with attachment to surface squamous epithelium and multiple cellular spindle cell nodules. Focal chondromyxoid matrix is noted. The epithelial component shows diffuse, strong immunoreactivity for cytokeratin and CK7. The spindle cells show variable to strong immunoreactivity with CK7, p63, SMMS and S100 (rare cells).

Differential diagnosis

Dermoid cyst:
- Cystic lesion lined by keratinizing squamous epithelium
- Epithelium associated with skin adnexal structures, such as sebaceous glands
Craniopharyngioma:
- Nests and cords of squamoid cells
- Peripheral palisaded nuclei
- Calcification and keratin material
Leiomyoma or leiomyosarcomas:
- Variably cellular proliferation of cells with blunt ended, cigar shaped nuclei
- Positive for SMA and desmin
- Absence of S100 positivity
Spindle cell rhabdomyosarcoma:
- Affects both children and adults
- Variably number of rhabdomyoblasts
- Positive for desmin, myogenin, MyoD1
Synovial sarcoma:
- Variable positivity for cytokeratins and TLE1
- Negative for SMA and MSA
- Characterized by t(X;18) SS18-SSX1/2 fusions
Respiratory epithelioid adenomatoid hamartoma (REAH):
- Noninvasive epithelial proliferation with surface invaginations with thickened basement membrane and ciliated respiratory epithelium
- Lack of spindle cell proliferation

Board review style question #1

Close observation
Cryotherapy
Neoadjuvant chemotherapy followed by surgical resection
Radiation therapy
Simple endoscopic or surgical resection

Board review style answer #1

E. Simple endoscopic or surgical resection

Salivary gland anlage tumor is a benign tumor with excellent prognosis following simple surgical resection. Of all the cases that have been reported, none has recurred following surgical excision.

Comment Here

Reference: Salivary gland anlage tumor

Board review style question #2

Diffuse S100 immunoreactivity in the spindled component
Distant metastasis and death within several months of initial diagnosis
Mesenchymal component with pleomorphic spindle cells showing significant cytologic atypia
Presence of ducts and squamous nests that blend into nodules of spindled cells
Presentation in an adolescent or young male

Board review style answer #2

D. Presence of ducts and squamous nests that blend into nodules of spindled cells

Salivary gland anlage tumor is a benign congenital tumor of infancy characterized histologically by the presence of both epithelial and mesenchymal components. Lined by nonkeratinizing squamous epithelium, in the submucosa are cellular stromal nodules composed of uniform, spindled to ovoid cells forming short fascicles, with duct-like epithelial structures and squamous nests in the periphery that blend into the cellular nodules. The spindle cells show variable to strong immunoreactivity with CK7, p63, SMMS and S100 (rare cells).

Comment Here

Reference: Salivary gland anlage tumor

Seromucinous hamartoma

Table of Contents

Case reports

54 year old man with large posterior nasal septal mass (Case of the Week #191)

Sinonasal carcinoma-general

Table of Contents

Definition / general

Rare and heterogenous group of malignancies that originate in the nasal cavity and paranasal sinuses and present with different histologic features and clinical behavior

Essential features

Sinonasal carcinomas are a rare and heterogeneous group of malignancies that develop in the nasal cavity and the paranasal sinuses with diverse histology
Most common are sinonasal squamous cell carcinoma and intestinal type adenocarcinomas
Clinical presentation of sinonasal malignancies is usually nonspecific and diagnosed at advanced stages with poor prognosis
Persistent exposure to wood and leather dust, textiles and organic solvents over a period of time is a strong risk factor for developing sinonasal carcinomas and is thought to be the result of chronic inflammation

ICD coding

ICD-10: C30.0 - malignant neoplasm of the nasal cavity

Epidemiology

Rare, < 1% of all human malignancies (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420, J Clin Med 2017;6:116)
Sinonasal cancers comprise 3% of all head and neck cancers (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420, J Clin Med 2017;6:116)
Affects 1 in 100,000 people per year worldwide (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Average age of presentation is between 50 - 70 years (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Epithelial tumors are the most common (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Originate from epithelial lining, accessory salivary glands, neuroendocrine tissue and olfactory epithelium
- Represent > 80% of all sinonasal tumors
The 2022 5th edition of the WHO Classification of Tumours of the nasal cavity, paranasal sinuses and skull base include the following epithelial malignancies (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420, Cancers (Basel) 2021;13:2835, Head Neck Pathol 2022;16:1)
- Squamous cell carcinoma
  - 50 - 80% of all sinonasal malignancies
  - ~60% of these are keratinizing, ~40% are nonkeratinizing, smaller number of other variants
- NUT carcinoma
  - Up to ~18% of upper aerodigestive tract poorly differentiated carcinomas
- SWI / SNF complex deficient sinonasal carcinoma
  - Rare, with most tumors showing loss of SMARCB1 (INI1)
- Sinonasal lymphoepithelial carcinoma
  - Strongly associated with Epstein-Barr virus infection, especially in endemic areas
- Sinonasal undifferentiated carcinoma
  - ~3 - 5% of sinonasal carcinomas
- Teratocarcinosarcoma (Turk Neurosurg 2017;27:468, Brain Tumor Res Treat 2020;8:57)
  - Extremely rare
  - Mostly middle aged adults with a mean age of 54.5 years
  - M:F = 7 - 8:1
- HPV related multiphenotypic sinonasal carcinoma (Ear Nose Throat J 2020;99:94)
  - Strong association with HPV, particularly HPV 33
  - Women affected more than men
  - Mean age at presentation in sixth decade
- Adenocarcinomas
  - Intestinal type adenocarcinoma represents ~20% of sinonasal malignancies
Sinonasal carcinomas occur more commonly in men (Nat Rev Clin Oncol 2014;11:460)
- M:F = 2:1 in squamous cell carcinoma
- M:F = 6:1 in intestinal type adenocarcinoma
Male predominance is thought to be a result of occupational exposure (Nat Rev Clin Oncol 2014;11:460)
Woodworkers have 500 - 900 times and 20 times the risk of developing intestinal type adenocarcinoma and squamous cell carcinoma, respectively (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Persistent exposure lasting longer than 20 years
- Association with woodworking not as strong outside of Europe, may reflect other susceptibility factors or exposure to different types of wood
Leather dust, glues, formaldehyde, chrome, nickel, flour, textiles and organic solvents have also been associated with sinonasal carcinomas, mostly squamous cell carcinoma (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Smoking is also a risk factor, although not as strongly associated as other head and neck cancers (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Smoking can increase the risk of squamous cell carcinoma 2 to 3 fold
HPV 16 and 18 are associated with squamous cell carcinoma (~30% of cases) (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Favorable prognosis
Other lower risk factors include nasal polyposis, inverted sinonasal papilloma, chronic sinusitis and radiotherapy used in the treatment of retinoblastoma (Curr Oncol 2021;28:2420)
- Squamous cell carcinoma can arise from the 3 types of Schneiderian papillomas (exophytic, inverted and oncocytic) (Head Neck Pathol 2016;10:60)
  - Very rare in exophytic type
  - Most commonly arise in inverted papillomas (~10%, although reportedly as high as 27%)
  - 4 - 17% in oncocytic type

Sites

Sinonasal tract comprises the nasal cavity, maxillary sinus, ethmoid sinus and sphenoid sinus (J Clin Med 2017;6:116)
- Includes the maxillary, ethmoid, nasal, frontal, palatine, sphenoid and lacrimal bones
- Lined with ciliated respiratory epithelium
Sinonasal squamous cell carcinoma occurs predominantly in the nasal cavity and maxillary sinuses (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Virtually all intestinal type adenocarcinomas are located in the olfactory groove of the ethmoid sinuses (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Other histologic subtypes can occur anywhere within the sinonasal cavity (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)

Pathophysiology

Organic dust and occupational exposures associated with tumor development are not considered directly mutagenic (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- These substances may cause chronic inflammation due to continuous mucosal irritation
- Chronic inflammation is a recognized mechanism of malignancy in several cancer types
Phagocytosis of inhaled organic dust, mineral fibers or fungal spores induce alveolar macrophages to secrete cytokines and chemokines involved in the inflammatory response, including (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Tumor necrosis factor (TNF) and IL1β, resulting in activation of transcription factor κβ (NFκβ)
- Expression of both NFκβ and cyclo-oxygenase 2 (COX2) are elevated in sinonasal carcinomas
Stimulation by wood dust results in the release of reactive oxygen species and reactive nitrogen species by alveolar macrophages (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Peroxynitrites and nitrogen oxides can generate mutagenic DNA adducts
- Strong relationship between nitric oxide production through inducible nitric oxide synthase activity and G > A nucleotide transitions in TP53 gene
- TP53 G > T transitions have been observed virtually exclusively in nonsmoking woodworkers
- G > A transitions in KRAS was the most frequent mutation found in patients with intestinal type adenocarcinoma with a history of exposure to wood and leather dust
Wnt / beta catenin pathway is also frequently affected (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Normally, beta catenin interacts with antigen presenting cell (APC) receptors, leading to ubiquitination of beta catenin
- When Wnt is overexpressed, beta catenin interacts with it and triggers translocation to the nucleus
  - Acts as a transcription factor for genes encoding cyclin D1 and c-MYC, leading to cell cycle dysregulation
- Activating mutations of Wnt are detected in 30 - 50% of paranasal sinus tumors
EGFR overexpression is found in 20 - 30% of sinonasal tumors (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Overexpression correlates with either amplification of EGFR gene or with hyperactivating point mutations
- EGFR overexpression is mutually exclusive with overexpression of p16, a surrogate marker of HPV infection
Metaplasia of the normal respiratory or olfactory epithelium is thought to occur in early stages of development (Nat Rev Clin Oncol 2014;11:460)
- Histopathologic change that represents cellular and tissue response to chronic inflammation
- Squamous metaplasia followed by dysplasia are histologic changes that precede sinonasal squamous cell carcinoma
  - Inverted papillomas are associated with a small proportion of sinonasal squamous cell carcinoma
  - HPV 16 infection has been described in ~30% of malignant tumors, suggestive of inverted papilloma as a precursor lesion to this subset of squamous cell carcinoma
- Cuboidal and intestinal metaplasia are proposed to be a precursor to intestinal type adenocarcinoma
- These metaplastic tissues have been observed adjacent to these tumors and in people with exposure to environmental or occupational risk factors
- Metaplastic tissues show a switch from normal sinonasal epithelial immunophenotype (CK7+ / CK20- / CDX2- / villin-) to an abnormal intestinal epithelium immunophenotype (CK7- / CK20+ / CDX2+ / villin+)

Etiology

Persistent environmental or occupational exposure to dust produced in the processing of wood, leather, flour, textiles, nickel and chrome (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Persistent exposure to glue, formaldehyde and organic solvents (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Smoking (Nat Rev Clin Oncol 2014;11:460)
Human papillomavirus infection (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
Radiotherapy for retinoblastoma (Curr Oncol 2021;28:2420)

Clinical features

Tumors grow locally and may extend into adjacent structures (Curr Oncol 2021;28:2420)
Clinical symptoms are often nonspecific (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Nasal obstruction, facial pain, persistent rhinorrhea or epistaxis
- Proptosis, diplopia or other neurologic symptoms may be seen in patients with advanced disease
Due to nonspecific nature of symptoms in early stages of disease, sinonasal malignancies may have a prolonged period of time before diagnosis (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)
- Lymph node metastasis at diagnosis in 10 - 20% of patients with sinonasal squamous cell carcinoma
- Lymphatic metastasis is rare in intestinal type adenocarcinoma, likely due to location and pattern of lymphatic drainage
On follow up, 10% of patients develop distant metastasis; rarely occurs without local recurrence (Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420)

Diagnosis

Rigid nasal endoscopy
Noninvasive imaging is essential in establishing the extent of the tumor (Nat Rev Clin Oncol 2014;11:460)
- Both CT and MRI should be performed to determine anatomic details on tumor localization and extension
- Critical in determining operability or planning radiotherapy
MRI is standard imaging modality for postoperative surveillance (Nat Rev Clin Oncol 2014;11:460)
Role of PET CT is important in staging of squamous cell carcinoma, allowing the identification of regional and distant metastases (Cancers (Basel) 2021;13:2835, Nat Rev Clin Oncol 2014;11:460)
Biopsy

Radiology description

Radiologic differentiation of sinonasal carcinomas is challenging due to overlap in imaging findings
Sinonasal squamous cell carcinomas show a soft tissue mass characterized by prominent bony destruction on CT (J Clin Med 2017;6:116, Head Neck Pathol 2016;10:1)
- MRI shows intermediate T1 signal intensity and hypointense T2 signal
- Variable enhancement on contrast enhanced T1 images that are less than half that of sinus mucosa
- Small lesions are homogenous in signal intensity
- Large tumors are more heterogenous with areas of necrosis and hemorrhage
Many imaging manifestations of adenocarcinoma are often indistinguishable from squamous cell carcinoma (J Clin Med 2017;6:116, Head Neck Pathol 2016;10:1)
- May show areas of calcification corresponding with mucin content
- Mucin producing adenocarcinomas may show hyperintensity on T2, while those without mucin may show isointensity to hypointensity on T2
Sinonasal undifferentiated carcinoma (J Clin Med 2017;6:116, Head Neck Pathol 2016;10:1)
- Noncalcified mass with variable contrast enhancement and areas of central necrosis on CT
- MRI shows isointensity on T1, isointensity to hyperintensity on T2 and heterogeneous enhancement on contrast enhanced T1
- Bony destruction and invasion into adjacent structures
- Difficult to distinguish from squamous cell carcinoma due to nonspecific findings

Radiology images

Images hosted on other servers:

CT of maxillary sinus squamous cell carcinoma

Maxillary sinus squamous cell carcinoma (CT)

CT of large exophytic squamous cell carcinoma

Large exophytic squamous cell carcinoma (CT)

Maxillary sinus adenocarcinoma (MRI)

Sinonasal undifferentiated carcinoma (CT)

SCC bone destruction (CT)

Prognostic factors

Prognostic factors include age, performance status, tumor location and local extension, the histologic subtype and whether perineural invasion is present
Carcinomas originating from the nasal cavity have a better prognosis than those from the paranasal sinuses
- This is attributed to nasal carcinomas producing symptoms that require earlier clinical attention
Among carcinomas arising from the maxillary sinuses, those originating from the anterior inferior portion have a better prognosis than those from the superior posterior portion
- This is attributed to superior posterior tumors having accessible structures such as the orbit or skull base
In T1 disease, 5 year survival is 80%; 30% in T4 disease
Extensive local disease increases both surgical morbidity and local recurrence within 2 years; for example, maxillary sinus tumors have a 30 - 70% 5 year survival with resection but this drops to 10 - 20% in unresectable cases
Intestinal type adenocarcinoma have a 50% 5 year survival after surgery and chemoradiation
- They usually grow locally, rarely involve regional lymph nodes and even more rarely give rise to distant metastases
- Papillary type and colonic type tumors have a better prognosis than solid or mucinous subtypes
- p53 and nuclear expression of beta catenin is associated with worse prognosis
Histologic grade does not have prognostic value in sinonasal squamous cell carcinoma but molecular markers do
- EGFR overexpression and HPV negativity in squamous cell carcinoma is associated with worse prognosis
- p16 overexpression with EGFR negativity has a better prognosis
References: Nat Rev Clin Oncol 2014;11:460, Curr Oncol 2021;28:2420

Case reports

36 year old man with a history of nasal blockage and left sided polypoid mass (J Clin Diagn Res 2016;10:ED12)
43 year old woman with disfiguring facial swelling with exophytic lesions protruding from nostrils (Cureus 2017;9:e1386)
61 year old man with squamous cell carcinoma arising from sinonasal inverted papilloma (AJNR Am J Neuroradiol 2020;41:1156)
68 year old man with rapidly progressive visual loss (Case Rep Oncol 2019;12:277)
69 year old woman with progressively worsening right eye visual acuity (Cureus 2019;11:e5281)

Treatment

Surgical resection has been the mainstay of sinonasal cancer management (Curr Oncol 2021;28:2420, Cancers (Basel) 2021;13:2835)
- Resection results in excellent control rates for T1 and T2 tumors
- For small, localized tumors, complete removal is possible with less invasive techniques (such as endoscopically)
Radiotherapy is given postoperatively in most cases, even if margins are negative (Curr Oncol 2021;28:2420)
Adjuvant chemotherapy is considered in cases of inadequate resection margin (Curr Oncol 2021;28:2420)
Radical neck dissection or elective radiation therapy of the whole neck for patients with positive neck lymph nodes (Curr Oncol 2021;28:2420)
Cisplatin or carboplatin with external beam radiation can be used for locally advanced and unresectable squamous cell carcinomas (Curr Oncol 2021;28:2420)
Concurrent chemoradiation can be used for those with comorbidities contraindicating surgery (Curr Oncol 2021;28:2420)
Intestinal type adenocarcinoma is typically less responsive to chemotherapy; use of radiotherapy is preferred (Curr Oncol 2021;28:2420)
Radiotherapy in conjunction with chemotherapy, when possible, is beneficial in locally advanced or unresectable disease (Curr Oncol 2021;28:2420)
Significant improvement in survival in patients treated with a combination of 2 or more multidisciplinary approaches (e.g., surgery, chemotherapy, radiotherapy) (Curr Oncol 2021;28:2420)

Clinical images

Images hosted on other servers:

Endoscopic view of squamous cell carcinoma

Exophytic squamous cell carcinoma

Gross description

Squamous cell carcinoma
- Soft, friable tan-white solid tumor
- Exophytic, papillary, polypoid, nodular or ulcerated mass
- May show hemorrhage and necrosis
Adenocarcinoma
- Tan-white cut surface
- May be flat, polypoid, exophytic, papillary, ulcerated, mucinous

Gross images

Contributed by Kelly Magliocca, D.D.S., M.P.H.

Maxillary sinus squamous carcinoma

Squamous carcinoma ex papilloma

HPV related multiphenotypic carcinoma

Maxillary sinus adenoid cystic

HPV associated adenosquamous carcinoma

Sinonasal intestinal type adenocarcinoma

Images hosted on other servers:

Craniectomy with squamous cell carcinoma

Microscopic (histologic) description

Squamous cell carcinoma (Head Neck Pathol 2016;10:60, Head Neck Pathol 2022;16:1)

Keratinizing squamous cell carcinoma
- Most common type, ~60%
- Morphologically identical to squamous cell carcinomas arising elsewhere
- Abundant, eosinophilic cytoplasm filled with keratin filaments
- Intercellular bridges prominent
- Stellate, irregular nests, cords or single tumor cells in desmoplastic stroma
- Keratinization and keratin pearl formation readily identifiable
- Graded as well, moderately or poorly differentiated
  - Well differentiated shows squamous epithelium with abundant keratinization, prominent intercellular bridges, with minimal pleomorphism and low mitotic activity
  - Moderately differentiated shows features between well and poorly differentiated, with focal keratinization
  - Poorly differentiated carcinomas have more nuclear atypia, pleomorphism, increased mitotic activity and minimal keratinization
Nonkeratinizing squamous cell carcinoma
- Squamous differentiation with minimal keratinization
- ~40% of all sinonasal squamous cell carcinomas
- Similar to the same tumor type arising in the oropharynx
- Blue cell tumor appearance with high N:C ratio, arranged in large, rounded nests or ribbons with smooth, usually well demarcated borders with little stromal desmoplasia
- Exophytic or inverted papillary architecture is common
- Minimal maturing squamous differentiation
- Prominent mitotic activity and apoptosis
- Central necrosis is common in nests
- Tumors tend to coat the mucosal surface with undulating, irregular contour
  - In areas where tumor invades downward, has inverted appearance with rounded nests, mimicking Schneiderian papilloma with carcinoma in situ
  - Combined with lack of stromal desmoplasia, gives a noninvasive appearance
- DEK::AFF2 subtype shows complex exophytic and endophytic growth
  - Broad papillary fronds, anastomosing lobules, ribbons and nests
  - Nuclear monotony and inflammatory infiltrate, especially neutrophils, typically present (Head Neck Pathol 2022;16:1)
  - Requires confirmation with DEK::AFF2 FISH break apart probe

NUT carcinoma (Head Neck Pathol 2022;16:1)

Composed of monotonous evenly spaced sheets of evenly sized nuclei that have vesicular chromatin and prominent nucleoli
Inflammatory infiltrate commonly seen
Abrupt keratinization may be seen in up to a third of cases

SWI / SNF complex deficient sinonasal carcinoma (Head Neck Pathol 2022;16:1, Am J Case Rep 2023;24:e939244)

Most common subtype is SMARCB1 deficient
Small to medium sized monomorphic basaloid cells, undifferentiated appearance
Indistinct cytoplasmic borders and round nuclei with variably prominent nucleoli
Up to a third of cases are more eosinophilic with plasmacytoid morphology, cytoplasmic vacuoles commonly seen
SMARCB1 deficient sinonasal carcinoma may occasionally be gland forming or yolk sac-like

Lymphoepithelial carcinoma (Curr Oncol 2021;28:2420, Ear Nose Throat J 2022;101:386)

Undifferentiated carcinoma with epithelial neoplastic cells accompanied by strong lymphocytic infiltrate
Characterized by medium to large sized polygonal epithelioid cells with vesicular nuclei and prominent nucleoli
Epithelioid cells form well circumscribed lobules or nests with dense mixed lymphoplasmacytic infiltrate
Increased mitoses with atypical forms
Dense lymphoid infiltrate may obscure epithelioid cells and mimic a lymphoproliferative disorder
Strong association with EBV, positive by in situ hybridization

Sinonasal undifferentiated carcinoma (Curr Oncol 2021;28:2420, Adv Anat Pathol 2020;27:51)

Undifferentiated polygonal medium to large cells arranged in nests, sheets, trabecular or solid patterns
Round blue cell tumor
Cells have round to oval hyperchromatic nuclei with variably prominent eosinophilic nucleoli and indistinct cell membranes
High N:C ratio
Strong mitotic activity with atypical forms
Frequently with necrosis, lymphovascular invasion and perineural invasion
Squamous, glandular or neuroectodermal differentiation should not be present

Teratocarcinosarcoma (J Oral Maxillofac Pathol 2016;20:147, Brain Tumor Res Treat 2020;8:57, Head Neck Pathol 2022;16:1)

Has features of carcinosarcoma and teratoma with varying degrees of maturity
Epithelial component typically consists of squamous epithelium and glandular structures
- May be benign or malignant
- Fetal appearing clear cell squamous epithelium is a characteristic finding
Mesenchymal component may show myofibroblastic cell proliferation with a loose myxoid stroma
Mature or immature mesenchymal elements seen (e.g., osteoid, cartilage, smooth or striated muscle)
Primitive neuroepithelial cells in sheets and nests
Cytologic atypia ranges from minimal to sarcomatous differentiation

HPV associated multiphenotypic sinonasal carcinoma (Ear Nose Throat J 2020;99:94, Head Neck Pathol 2022;16:1)

Histologic and immunophenotypic features of both salivary gland type carcinoma and squamous cell carcinoma
- Biphasic ductal and myoepithelial differentiation, frequently in a cribriform arrangement reminiscent of adenoid cystic
- Frequent squamous cell carcinoma in situ, occasional squamous differentiation within invasive tumor
Myoepithelial features show cytoplasmic clearing, plasmacytoid appearance and spindling
May show sarcomatous transformation and cartilaginous differentiation
May see surface squamous dysplasia
High mitotic rate and areas of necrosis are frequently seen

Adenocarcinoma (Curr Oncol 2021;28:2420, Head Neck Pathol 2016;10:68)

20% of malignant neoplasms in the sinonasal tract
Arises from either lining surface epithelium or seromucinous glands
3 main types: intestinal type, nonintestinal type and salivary type
Intestinal type adenocarcinoma
- Originates from Schneiderian mucosa and is the most frequent type of adenocarcinoma (~6 - 13%)
- May recapitulate normal intestinal mucosa with villi and specialized cell types (e.g., goblet, Paneth)
- Similar features to adenomas and colorectal adenocarcinoma
- Cribriform glands with necrotic debris in lumen (dirty necrosis)
- Histologic types (modified Barnes classification): colonic, papillary, solid, mucinous, mixed
  - Colonic type is most common (~40 - 50%)
    - Glandular, tubular and trabecular architecture
    - Rare papillae
    - Glands lined by crowded columnar cells with anisonucleosis
    - Intracellular and extracellular mucin and goblet cells may be present
  - Papillary type
    - Papillary architecture predominant with occasional tubular elements with minimal cytologic atypia
    - May have columnar goblet cells mimicking intestinal adenomas
  - Solid type
    - Less differentiated with solid and trabecular architecture
    - Minimal cytologic atypia with rare mitosis
  - Mucinous
    - Mimics mucinous variants of colorectal carcinoma
    - Mucin filled glands or cell clusters that float in pools of extracellular mucin
Nonintestinal type adenocarcinoma
- Does not display features of either intestinal type or salivary type
- Morphologically heterogeneous
- Back to back small glands or acini
- Divided into high grade and low grade
- High grade
  - More poorly differentiated with marked nuclear pleomorphism
  - Glandular and papillary growth patterns
  - Mitoses readily identifiable
  - Tumor necrosis and apoptosis are frequently seen
- Low grade
  - Varied with exophytic papillae and tubular or glandular patterns
  - Papillae and glands lined by single layer of uniform columnar or cuboidal cells with minimal cytologic atypia and inconspicuous nucleoli
  - Mild to moderate cellular pleomorphism and rare mitoses
  - Tumor necrosis is not typically seen
- Sinonasal renal cell-like adenocarcinoma (Cureus 2021;13:e14285, Head Neck Pathol 2008;2:75, Head Neck Pathol 2022;16:1)
  - Rare
  - Morphologically similar to clear cell renal cell carcinoma with monotonous cuboidal to polyhedral cells with abundant clear cytoplasm
  - Intranuclear holes may be seen
  - Predominantly solid to nested, glandular growth pattern with fibrous septa and prominent vascularity
  - Immunohistochemistry can distinguish from clear cell renal cell carcinoma
  - Positive: CK7, CAIX, CD10; negative: RCC, PAX8 (Medicine (Baltimore) 2017;96:e7711)

Microscopic (histologic) images

Contributed by Wai Szeto, M.D., M.S.

Squamous cell carcinoma and inverted papilloma

Squamous cell carcinoma and inverted papilloma

Intestinal type adenocarcinoma

Maxillary nonintestinal type adenocarcinoma

Sinonasal undifferentiated carcinoma

Sinonasal undifferentiated carcinoma mitotic activity

Nonintestinal type adenocarcinoma (CK7)

Nonintestinal type adenocarcinoma (SOX10)

Sinonasal undifferentiated carcinoma (pancytokeratin+)

Retained INI1

Virtual slides

Images hosted on other servers:

Sinonasal undifferentiated carcinoma

Positive stains

Squamous cell carcinoma (Head Neck Pathol 2014;8:269, Am J Surg Pathol 2017;41:458)
- AE1 / AE3, CK5/6, CK7, CK903
- p40, p63
- EMA
- Nonkeratinizing squamous cell carcinoma
  - p16 should be diffuse, block-like, with nuclear and cytoplasmic staining in > 70% of neoplastic cells
  - SMARCB1 (INI1) and SMARCA4 (BRG1) retained
NUT carcinoma (Am J Surg Pathol 2012;36:1216, Head Neck Pathol 2022;16:1)
- NUT1 in diffuse speckled pattern
- Pancytokeratin, p40 and p63 in majority of cases
- INI1 retained
SWI / SNF complex deficient sinonasal carcinoma (Am J Surg Pathol 2017;41:458, Am J Case Rep 2023;24:e939244)
- Pancytokeratin
- p63, CK5 and CK7 in ~50% of cases
- Synaptophysin, chromogranin, CD56 and CD117 may occasionally show positivity
- p16 may show diffuse positivity but negativity for HPV by in situ hybridization
Lymphoepithelial carcinoma (Semin Diagn Pathol 2015;32:74)
- Pancytokeratin
- EBER by in situ hybridization
Sinonasal undifferentiated carcinoma (Mod Pathol 2017;30:S1, Mod Pathol 2019;32:205, Arch Pathol Lab Med 2015;139:55, Curr Oncol 2021;28:2420)
- AE1 / AE3, CAM5.2, EMA
- CK7, CK8, CK19
- p16 and CD117 may show diffuse positivity
  - Not associated with HPV despite p16 positivity
- SMARCB1 (INI1) and SMARCA4 (BRG1) retained
- IDH R172S / T can detect IDH mutation
Teratocarcinosarcoma (J Oral Maxillofac Pathol 2016;20:147, Brain Tumor Res Treat 2020;8:57, Head Neck Pathol 2022;16:1, Head Neck Pathol 2022;16:229)
- Complex immunoprofile due to many immunohistochemical stains highlighting different components
- Cytokeratins, AE1 / AE3, CAM5.2, CK5/6, EMA in epithelial components
- Desmin, vimentin, SMA in mesenchymal components
- S100, synaptophysin, chromogranin, CD56, CD99, INSM1, GFAP, NSE in immature neuroectodermal components
HPV associated multiphenotypic sinonasal carcinoma (Head Neck Pathol 2019;13:331, Am J Surg Pathol 2017;41:1690, Head Neck Pathol 2019;13:220, Ear Nose Throat J 2020;99:94)
- p16 shows strong, block-like positivity
- Pancytokeratin
- Basaloid cells positive for p40, p63, calponin, SMA, SOX10
- CD117 in ductal cells
- S100
- MYB variable (but negative for gene fusion by FISH)
- LEF1 strong nuclear expression
- INI1 retained
Intestinal type adenocarcinoma (Head Neck Pathol 2017;11:295, Head Neck Pathol 2016;10:68)
- Pancytokeratin
- CK7, CEA and EMA are variably positive
- Intestinal markers: CK20, CDX2, villin, SATB2, MUC2
- Neuroendocrine markers may be focally positive (chromogranin, synaptophysin)
- Aberrant p53 expression
Nonintestinal type adenocarcinoma (Head Neck Pathol 2016;10:68)
- Pancytokeratin: AE1 / AE3, MNF116, OSCAR
- CK7
- May show positivity for DOG1, SOX10 and S100

Negative stains

Squamous cell carcinoma (Head Neck Pathol 2014;8:269, Am J Surg Pathol 2017;41:458)
- CD99, S100, SOX10, NUT
NUT carcinoma (Am J Surg Pathol 2012;36:1216, Head Neck Pathol 2022;16:1)
- Synaptophysin, chromogranin, S100 (may be focal)
SWI / SNF complex deficient sinonasal carcinoma (Am J Surg Pathol 2017;41:458, Am J Case Rep 2023;24:e939244)
- INI1 (characteristic)
- CD99, NKX2.2, NUT1, S100
Lymphoepithelial carcinoma (Semin Diagn Pathol 2015;32:74)
- p16 typically negative
Sinonasal undifferentiated carcinoma (Mod Pathol 2017;30:S1, Mod Pathol 2019;32:205, Arch Pathol Lab Med 2015;139:55, Curr Oncol 2021;28:2420)
- Absent to minimal expression of lineage specific markers
  - p40, p63, CK5/6, CEA, CD34, desmin, SMA, SMMHC, S100, calretinin, CD45
  - May show weak or patchy expression of neuroendocrine markers (synaptophysin, chromogranin, CD56)
Teratocarcinosarcoma (J Oral Maxillofac Pathol 2016;20:147, Brain Tumor Res Treat 2020;8:57, Head Neck Pathol 2022;16:1, Head Neck Pathol 2022;16:229)
- SMARCA4 (BRG1) loss
- Β hCG, CD45
HPV associated multiphenotypic sinonasal carcinoma (Head Neck Pathol 2019;13:331, Am J Surg Pathol 2017;41:1690, Head Neck Pathol 2019;13:220, Ear Nose Throat J 2020;99:94)
- Androgen receptor, desmin, NUT1, synaptophysin, chromogranin, CD56
Intestinal type adenocarcinoma (Head Neck Pathol 2017;11:295, Head Neck Pathol 2016;10:68)
- Annexin A1 loss
- Annexin A2 decreased
Nonintestinal type adenocarcinoma (Head Neck Pathol 2016;10:68)
- CK20, CDX2, villin, MUC2
- Neuroendocrine markers

Molecular / cytogenetics description

Nonkeratinizing squamous cell carcinoma
- p16 positive cases should be followed by high risk HPV ISH or PCR for confirmation (Cancers (Basel) 2022;14:1874)
- DEK::AFF2 fusion with RNA sequencing or DEK break apart FISH in DEK::AFF2 carcinoma (Am J Surg Pathol 2021;45:1682)
Lymphoepithelial carcinoma (Head Neck Pathol 2022;16:1)
- EBER ISH positive
Sinonasal undifferentiated carcinoma
- IDH2 R172 mutation is common (> 80%) (Mod Pathol 2019;32:205)
NUT carcinoma (Head Neck Pathol 2013;7:11, Head Neck Pathol 2022;16:1)
- Rearrangement of NUT gene, most commonly BRD4::NUT [t(15;19)(q14, p13.1)]
- Remaining cases are BRD3::NUT [t(9;15)(q34.2;q14)] or other NUT variant fusions
HPV associated multiphenotypic sinonasal carcinoma (Head Neck Pathol 2019;13:331, Am J Surg Pathol 2017;41:1690, Head Neck Pathol 2019;13:220, Ear Nose Throat J 2020;99:94)
- High risk HPV positive by DNA or RNA ISH and PCR
- HPV 33 is most commonly isolated
- Negative for MYB, MYBL1 or NFIB gene fusions that are seen in adenoid cystic carcinoma

Sample pathology report

Nasal contents, biopsy:
- Undifferentiated carcinoma, most consistent with sinonasal undifferentiated carcinoma (see comment)
- Comment: Sections show a poorly differentiated epithelioid neoplasm growing in nests, sheets and trabeculae. Numerous mitotic figures are identified. Focal necrosis is present. The tumor cells have mild nuclear pleomorphism and prominent nucleoli. No overt squamous or glandular differentiation is identified. By immunohistochemical staining, the tumor is positive for pankeratin and CK7. The tumor is negative for synaptophysin, chromogranin, CK5/6, p40, p63, SMMS, S100, SOX10, myogenin and desmin. INI1 immunostain is retained. EBV EBER in situ hybridization is negative. Overall morphology and immunophenotypic profile are most consistent with sinonasal undifferentiated carcinoma.

Differential diagnosis

Squamous cell carcinoma (Head Neck Pathol 2016;10:68):
- Schneiderian papillomas (inverted, exophytic, oncocytic):
  - Lacks invasive growth
  - Mild atypia
- Basaloid squamous cell carcinoma:
  - Basaloid variant that grows in nests / nodules with peripheral palisading
NUT carcinoma (Mod Pathol 2019;32:205, Head Neck Pathol 2022;16:1, Int J Surg Pathol 2022;30:273, Head Neck Pathol 2016;10:85, Curr Oncol 2021;28:2420):
- Basaloid squamous cell carcinoma:
  - p40, p63 positivity
  - NUT1 negative
- Sinonasal undifferentiated carcinoma:
  - NUT1 negative
  - IDH2 mutations frequently present
- Neuroendocrine carcinoma:
  - Lacks keratinization
  - Positivity for synaptophysin, chromogranin, CD56, NSE
- SWI / SNF complex deficient sinonasal carcinoma:
  - Loss of INI1
  - NUT1 negative
SWI / SNF complex deficient sinonasal carcinoma (Am J Surg Pathol 2017;41:458, Am J Case Rep 2023;24:e939244, Head Neck Pathol 2022;16:1, Head Neck Pathol 2016;10:85, Curr Oncol 2021;28:2420):
- Sinonasal undifferentiated carcinoma:
  - INI1 retained
  - IDH2 mutations frequently present
- NUT carcinoma:
  - NUT1 positive
- Neuroendocrine carcinoma:
  - Positivity for synaptophysin, chromogranin, CD56, NSE
- HPV associated multiphenotypic sinonasal carcinoma:
  - p16 shows strong, block-like positivity
  - HPV positive by ISH and PCR
  - INI1 retained
Lymphoepithelial carcinoma (Cureus 2022;14:e31103, Mod Pathol 2017;30:S1):
- Sinonasal undifferentiated carcinoma:
  - Typically, does not have a prominent lymphoid infiltrate
  - EBV negative
- Nonkeratinizing squamous cell carcinoma:
  - Difficult to distinguish as the immunohistochemical profile will be virtually identical
- Melanoma:
  - Positive for melanocytic markers such as SOX10, HMB45, S100, PRAME, MelanA
- Lymphoma:
  - Hematolymphoid markers showing B or T cell lineage
Sinonasal undifferentiated carcinoma (CA Cancer J Clin 2023;73:72, Head Neck Pathol 2016;10:68):
- Neuroendocrine carcinoma:
  - Shows nuclear molding, salt and pepper chromatin
  - Strong positivity with neuroendocrine marker (synaptophysin, chromogranin, NSE)
- Nonkeratinizing squamous cell carcinoma:
  - May show focal keratinization
  - p16 positivity
  - p40, p63, CK5/6 positive
  - CK7 negative in nonkeratinizing squamous cell carcinoma
    - CK7 positive; p40, p63, CK5/6 negative in sinonasal undifferentiated carcinoma
- Keratinizing squamous cell carcinoma:
  - p40, p63 and CK5/6 positive in keratinizing squamous cell carcinoma; negative in sinonasal undifferentiated carcinoma
- NUT carcinoma:
  - Diffuse nuclear staining with NUT
- Lymphoma:
  - Hematolymphoid markers showing B or T cell lineage
Teratocarcinosarcoma (Brain Tumor Res Treat 2020;8:57, Head Neck Pathol 2022;16:1):
- Olfactory neuroblastoma:
  - Mesenchymal differentiation not present
- Carcinosarcoma:
  - Neuroectodermal differentiation not present
HPV associated multiphenotypic sinonasal carcinoma (Ear Nose Throat J 2020;99:94, Head Neck Pathol 2022;16:1)
- Adenoid cystic carcinoma:
  - MYB, MYBL1 or NFIB translocations present
- Squamous cell carcinoma:
  - Lacks biphasic ductal and myoepithelial cell differentiation
- SWI / SNF complex deficient sinonasal carcinoma:
  - Loss of INI1
  - HPV negative
- Sinonasal undifferentiated carcinoma:
  - IDH2 mutations frequently present
  - HPV negative
  - Diagnosis of exclusion
Intestinal type adenocarcinoma (Head Neck Pathol 2016;10:68):
- Metastatic adenocarcinoma of colonic origin:
  - Rare but must be considered
  - Morphology and immunohistochemistry are virtually indistinguishable from a GI primary
  - Exclusion primarily based on clinical and radiographic correlation
- Sinonasal nonintestinal type adenocarcinoma:
  - Back to back small glands or acini that lack mucinous differentiation
  - Negative for CK20, CDX2 and villin
- Salivary gland type adenocarcinomas:
  - Negative for CK20, CDX2 and villin
Nonintestinal type adenocarcinoma (Head Neck Pathol 2016;10:68):
- Sinonasal intestinal type adenocarcinoma:
  - Morphologically similar to colorectal adenocarcinomas
  - Cribriform glands with dirty necrosis, goblet cells
  - Positive for CK20, CDX2 and villin
- Salivary gland type adenocarcinomas:
  - Morphologically diverse
  - Most common is adenoid cystic
  - Follows immunophenotype of respective salivary gland type adenocarcinoma

Board review style question #1

The image above depicts a tumor in the nasal cavity, which is characterized by mutations in the IDH1 or IDH2 genes. What is your most likely diagnosis?

Adenoid cystic carcinoma
Intestinal type adenocarcinoma
Sinonasal squamous cell carcinoma
Sinonasal undifferentiated carcinoma

Board review style answer #1

D. Sinonasal undifferentiated carcinoma. IDH1 or IDH2 mutations are common in sinonasal undifferentiated carcinoma and can be seen in more than 80% of cases. The most common is the IDH2 R172 mutation, which can be detected with immunohistochemistry. Answers A - C are incorrect because these mutations are not typically associated with those entities.

Comment Here

Reference: Sinonasal carcinoma-general

Board review style question #2

A biopsy from a mass in the maxillary sinus showed histologic features of squamous cell carcinoma with a complex exophytic and endophytic growth pattern with broad papillary fronds. There is minimal keratinization. Which of the following gene rearrangements is frequently observed in this type of tumor?

CASG::PRKD1 fusion
CRTC1::MAML2 fusion
DEK::AFF2 fusion
MYB::NFIB fusion

Board review style answer #2

C. DEK::AFF2 fusion. DEK::AFF2 is a novel fusion identified in a type of nonkeratinizing squamous cell carcinoma of the sinonasal tract called DEK::AFF2 fusion associated papillary squamous cell carcinoma that exhibits complex exophytic and endophytic growth with broad papillary fronds, anastomosing lobules, ribbons and nests. Detectable with DEK::AFF2 FISH break apart probe or RNA sequencing. Answer A is incorrect because CASG::PRKD1 is associated with polymorphous adenocarcinoma. Answer B is incorrect because CRTC::MAML2 is associated with mucoepidermoid carcinoma. Answer D is incorrect because MYB::NFIB is associated with adenocystic carcinoma.

Comment Here

Reference: Sinonasal carcinoma-general

Sinonasal glomangiopericytoma

Table of Contents

Definition / general

Uncommon soft tissue tumor of perivascular myoid differentiation with hemangiopericytoma-like vasculature

Essential features

Also called glomangiopericytoma, sinonasal type
Nasal cavity is usually affected, present with nasal obstruction, mass, epistaxis and sinusitis
CTNNB1 mutation with beta catenin oncogenic activation (beta catenin nuclear staining on IHC) (Head Neck Pathol 2019;13:298, Yale J Biol Med 2021;94:593)
Excellent long term outcome with surgery alone, recurrence rate ~27%

Terminology

Previous name: sinonasal type hemangiopericytoma
Glomus tumor
Intranasal myopericytoma

ICD coding

ICD-10: D38.5 - neoplasm of uncertain behavior of other respiratory organs

Epidemiology

Rare, comprising < 0.5% of sinonasal primary neoplasms (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Broad age range (5 - 90 years); mean in seventh decade
F > M (1.2:1)
No difference in outcome based on gender after surgery

Sites

Nasal cavity is usually affected, turbinate and septum occasionally affected in isolation (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Maxillary and ethmoid sinuses may also be affected in conjunction with nasal cavity
Bilateral tumor uncommon (~5%)

Pathophysiology

May arise from pericytes associated with vessels of nasal cavity
Mutational activation of beta catenin (Head Neck Pathol 2019;13:298, Yale J Biol Med 2021;94:593)
Associated with cyclin D1 overexpression (Pathol Res Pract 2019;215:983)

Etiology

CTNNB1 mutations

Clinical features

Nasal obstruction, mass, polyps, difficulty breathing
Sinusitis, discharge, change in smell
Nasal bleeding (J Pak Med Assoc 2020;70:2469)
Headache
Rare association with oncogenic osteomalacia (BMC Endocr Disord 2022;22:31)

Diagnosis

Clinical symptoms and polypoid mass identified in the nasal cavity
CT and MRI showing a polypoid mass of nasal cavity (paranasal sinus) accompanied with bone erosion or sclerosis
Biopsy showing soft tissue with perivascular myoid differentiation, positive for beta catenin nuclear staining, cyclin D1 and SMA, negative for vascular markers in the tumor cells (Pathol Res Pract 2019;215:983)

Laboratory

In the majority of cases, lab tests do not help
In rare cases, associated with osteomalacia: serum hypophosphatemia and elevated alkaline phosphatase (BMC Endocr Disord 2022;22:31)

Radiology description

CT and MRI showing a mass of nasal cavity (paranasal sinus), could be lobulated

Radiology images

Contributed by Jinping Lai, M.D., Ph.D.

Right nasal mass (MRI axial)

Right nasal mass (MRI coronal)

Right nasal mass (MRI sagittal)

Prognostic factors

Excellent prognosis after surgery (5 year survival ~90%)
Recurrence rate ~27%, long term clinical follow up advocated as recurrences may develop late (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Recurrences are associated with long duration of the symptoms, bone invasion and profound nuclear pleomorphism

Case reports

42 year old woman with osteomalacia caused by sinonasal glomangiopericytoma and coexisting parathyroid adenoma (BMC Endocr Disord 2022;22:31)
57 year old man with sinonasal FUS::ERG rearranged Ewing sarcoma mimicking glomangiopericytoma (Case Rep Oncol 2020;13:1393)
60 year old man with new onset, right arm and leg weakness / numbness, was found to have a left ethmoid sinus glomangiopericytoma with extension in the olfactory fossa (Yale J Biol Med 2021;94:593)
70 year old man with nasal blockage and epistaxis underwent endoscopic sinus surgery (J Pak Med Assoc 2020;70:2469)
74 year old man with a reddish nasal mass with CTNNB1 p.S37C mutation (Head Neck Pathol 2019;13:298)

Treatment

Surgery (polypectomy or wide surgical resection) is the treatment of choice (J Pak Med Assoc 2020;70:2469)
Radiation could be used for nonsurgical candidates

Clinical images

Contributed by Jinping Lai, M.D., Ph.D.

Nasal endoscopy

Gross description

Polypoid mass, mean 3 cm, beefy red to grayish pink with hemorrhage
Soft, edematous and fleshy cut surface

Gross images

Contributed by Jinping Lai, M.D., Ph.D.

Cut surface

Frozen section description

Frozen sections of the tumor show subepithelial cytologically bland spindle and round cell proliferation separated from the surface respiratory epithelium, hemorrhagic stromal, perivascular hyalinization and staghorn vessels

Frozen section images

Contributed by Jinping Lai, M.D., Ph.D.

Subepithelial grenz zone, hemorrhagic stroma

Perivascular proliferation and hyalinization

Perivascular proliferation / hyalinization

Perivascular proliferation and staghorn vessels

Microscopic (histologic) description

Surface respiratory epithelium or metaplastic squamous epithelium is intact
Subepithelial proliferation separated from surface (grenz zone)
Diffuse growth with fascicular, solid or focally whorled pattern of spindled or round / oval tumor cells that arrange themselves around prominent, small, thin walled submucosal blood vessels
Cells have variable cytoplasm and nuclei, indistinct cell borders and occasionally are multinucleated
Minimal atypia, no necrosis, no / rare mitotic activity
Vessels are prominent with staghorn appearance and perivascular hyalinization
Inflammatory cells including mast cells and eosinophils are often present

Microscopic (histologic) images

Contributed by Jinping Lai, M.D., Ph.D.

Subepithelial grenz zone and whorled features

Perivascular hyalinization and staghorn vessels

No mitosis, eosinophils

Beta catenin nuclear staining

Positive cyclin D1

Positive CD99

Positive SMA

Low Ki67 index

Cytology description

Smears show spindled, epithelioid or round cells with indistinct cell borders

Positive stains

Beta catenin: nearly all tumor cells with nuclear and cytoplasmic staining (Pathol Res Pract 2019;215:983, Yale J Biol Med 2021;94:593)
Cyclin D1, CD99 (Pathol Res Pract 2019;215:983)
Vimentin (98%), smooth muscle actin (92%), muscle specific actin (77%), factor XIIIa (78%), laminin (52%)
D2-40 (Virchows Arch 2006;448:459)

Negative stains

ERG, CD31, CD34 (usually), factor VIII, keratin

Electron microscopy description

Basal lamina surrounds individual cells, tapered cytoplasmic extensions, orderly bundles of filaments (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)

Molecular / cytogenetics description

CTNNB1 mutation: PCR and gene sequencing show single nucleotide substitutions with exon 3 codons of the CTNNB1 glycogen serine kinase 3 beta phosphorylation region

Sample pathology report

Right nasal cavity mass, biopsy:
- Nasal glomangiopericytoma (see comment)
- Comment: Sections of the nasal mass biopsy show cytologically bland spindle cell proliferation with scattered staghorn vessels and perivascular hyalinization. The tumor cell proliferation is separated from the overlying respiratory epithelium. No mitotic figures or tumor necrosis is identified. The tumor cells are positive for beta catenin (nuclear staining), cyclin D1, CD99 and SMA, negative for desmin, CD31, ERG, CD34 and AE1 / AE3. The histologic features and immunoprofile support the diagnosis.

Differential diagnosis

Glomus tumor:
- Also a pericytic tumor with similar staining but extremely rare in the sinonasal region
- Composed of compact epithelioid cells
- Positive for SMA but negative for beta catenin nuclear staining
Lobular capillary hemangioma:
- Lobular pattern at low power
- Has spindled fibroblasts and prominent vessels but overall granulation tissue-like appearance with only small capillaries
- Positive for CD34 and CD31, negative for beta catenin nuclear staining
Solitary fibrous tumor:
- Similar vascular pattern but tumor has patternless pattern, with ropy keloidal collagen and thin walled vascular spaces
- Positive for CD34 and STAT6, negative for beta catenin nuclear staining
Ewing or Ewing-like sarcoma:
- Tumor cells have clear cytoplasm and similar histology with positive CD99 immunoreactivity
- Negative beta catenin nuclear staining and positive for EWSR1 rearrangement (Case Rep Oncol 2020;13:1393)

Additional references

Head Neck Pathol 2020;14:459

Board review style question #1

Regarding sinonasal glomangiopericytoma, which of the following statements is true?

Bilateral tumor is seen in 10% of patients
It is much more common in male patients
Majority of the tumors have a poor prognosis
Maxillary sinus is the most affected
Nasal cavity is usually affected

Board review style answer #1

E. Nasal cavity is usually affected; maxillary and ethmoid sinuses may also be affected in conjunction with nasal cavity. The female to male ratio is 1.2 to 1. Patients with bilateral tumor are uncommon (~5%). The majority of the tumors have a good prognosis.

Comment Here

Reference: Sinonasal glomangiopericytoma

Board review style question #2

A 50 year old woman presented with right nasal obstruction and occasional nose bleeding. Physical examination showed a red to grayish polypoid soft mass in her right nasal cavity and a biopsy was performed. A histology photo is shown above. Which of the following immunostains should be positive for the diagnosis of nasal glomangiopericytoma?

Beta catenin nuclear staining
CD31
CD34
S100 nuclear staining
STAT6 nuclear staining

Board review style answer #2

A. Beta catenin nuclear staining should be positive in the tumor cells, as sinonasal glomangiopericytoma is related to mutational beta catenin activation. Positive CD34 and STAT6 are helpful for diagnosis of solid fibrous tumor. Positive S100 and muscular markers are helpful for diagnosis of biphenotypic sinonasal sarcoma.

Comment Here

Reference: Sinonasal glomangiopericytoma

Sinonasal lymphoepithelial carcinoma (pending)

[Pending]

Sinonasal papilloma

Table of Contents

Definition / general

Sinonasal papilloma is a benign epithelial neoplasm of sinonasal tract
WHO has divided sinonasal papilloma into 3 distinct types (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017):
- Inverted papilloma
- Exophytic papilloma
- Oncocytic papilloma

Essential features

Comparison of essential features of the 3 types of sinonasal papilloma
	Inverted papilloma	Exophytic papilloma	Oncocytic papilloma
Frequency	Most common	Second most common	Least common
Location	Lateral nasal wall / paranasal sinus	Nasal septum	Lateral nasal wall / paranasal sinus
Male to female ratio	2 - 3:1	10:1	1:1
Most common age of presentation	5th to 6th decades	3rd to 5th decades	5th to 6th decades
Association with human papillomavirus (HPV)	High risk HPV Low risk HPV	Low risk HPV	No association
Architectural pattern	Endophytic (inverted)	Exophytic (filiform)	Exophytic or endophytic
Epithelial lining	Squamous, transitional or respiratory	Squamous, transitional or respiratory	Oncocytic
Molecular alterations	EGFR activating mutation	None reported	KRAS mutation
Risk of malignant transformation	5 - 15%	~0%	4 - 17%

Terminology

Other terminologies that have been used in the literature and previous versions of WHO classification include:
- All types: Schneiderian papilloma and epithelial papilloma
- Exophytic type: transitional cell papilloma, fungiform papilloma, Ringertz papilloma and septal papilloma
- Oncocytic type: cylindrical cell papilloma and columnar cell papilloma

ICD coding

ICD-O: 8121/1
ICD-10: D14.0

Epidemiology

Annual incidence is 0.74 - 2.3 per 100,000 population (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
Inverted papilloma is the most common subtype, followed by exophytic papilloma; oncocytic papilloma is the least common
Inverted and oncocytic papilloma most commonly affect patients in their 5th to 6th decades, while exophytic papilloma occurs in 3rd to 5th decades
Inverted and exophytic papilloma occur more frequently in males, with a male to female ratio of 2 - 3:1 and 10:1, respectively; oncocytic papilloma affects both genders equally (Head Neck Pathol 2017;11:269)

Sites

Sinonasal papilloma commonly affects nasal cavity or paranasal sinuses
Exophytic papilloma is typically located in the nasal septum, while the inverted and oncocytic types predominantly affect lateral nasal wall or paranasal sinuses
Inverted papilloma may secondarily extend to nonsinonasal sites, e.g. pharynx, ear, cranial cavity
Sinonasal papilloma is usually unilateral; bilateral involvement is rare

Etiology

Role of high risk human papillomavirus (HPV) in inverted papilloma remains controversial
- Reported rate of high risk HPV in inverted papilloma and carcinoma ex inverted papilloma ranges from 0 - 100% (World J Otorhinolaryngol Head Neck Surg 2016;3:54, Head Neck Pathol 2017;11:269)
- WHO gives a frequency of 38.5% in inverted papilloma (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
Low risk HPV, especially types 6 and 11, has also been detected in inverted papilloma and is more common than high risk HPV
Other etiologic factors implicated in inverted papilloma include exposure to welding, organic solvents and smoking (World J Otorhinolaryngol Head Neck Surg 2016;3:54)
Exophytic papilloma may be related to low risk HPV, especially types 6 and 11
No significant association between oncocytic papilloma and HPV (Head Neck Pathol 2017;11:269)

Clinical features

Symptoms are usually nonspecific, including nasal congestion, nasal obstruction, nasal discharge or epistaxis

Diagnosis

Relies on histology in biopsy or surgical resection

Radiology images

Images hosted on other servers:

CT findings of an inverted papilloma

MRI findings of an inverted papilloma

Prognostic factors

Increased risk of recurrence if involvement of sphenoid sinus, frontal sinus or maxillary sinus walls other than medial or extrasinus extension (Biomed Res Int 2017;2017:9195163)
Major cause of recurrence is incomplete resection
Risk of malignant transformation is ~9% in inverted papilloma (range: 5 - 15%) (Eur Arch Otorhinolaryngol 2017;274:2991)
4 - 17% of oncocytic papilloma undergo malignant transformation
Exophytic papilloma is not associated with an increased incidence of carcinoma

Case reports

46 year old man with inverted papilloma of the middle ear (Braz J Otorhinolaryngol 2012;78:122)
48 year old man and 56 year old man with inverted papilloma of the maxillary sinus (Rom J Morphol Embryol 2016;57:289)
60 year old man with inverted papilloma of the lacrimal sac (J Cancer Res Ther 2015;11:238)
74 year old woman with inverted papilloma of the temporal bone (BMJ Case Rep 2013;2013:bcr2013201219)
82 year old man with oncocytic papilloma of the maxillary sinus mimicking lymphoma (Medicine (Baltimore) 2016;95:e4646)

Treatment

Complete surgical excision through endoscopic surgery or open radical procedure is the treatment of choice (Clin Otolaryngol 2006;31:499)
Aim is to completely remove all diseased mucosa; lateral rhinotomy and medial maxillectomy may be required for inverted or oncocytic papilloma
If treated with local excision only, 50 - 70% may recur, particularly for inverted subtype

Clinical images

Images hosted on other servers:

Squamous papilloma

Endoscopic image
of an inverted
papilloma

Gross description

Inverted papilloma: pink-tan-gray, soft to moderately firm polypoid growth with convoluted or wrinkled surface
Exophytic papilloma: usually mushroom shaped and exophytic with papillary appearance
Oncocytic papilloma: fleshy polypoid growth of variable color
Generous or complete sampling is advised to search for focus of malignant transformation

Gross images

Images hosted on other servers:

Inverted papilloma

Microscopic (histologic) description

Inverted papilloma:

Architecture: prominent downward endophytic growth of round to elongated interconnected epithelial nests with smooth outer contour
Epithelium is hyperplastic (5 - 30 cell layers in thickness) and may be of squamous, transitional or respiratory type
Transmigrating neutrophils and neutrophilic microabscesses may be seen
Stroma may have edema or chronic inflammation
Seromucinous gland in the lamina propria is commonly decreased or absent

Exophytic papilloma:

Architecture: filiform or papillary arrangement with delicate fibrovascular core
Epithelial lining can be either squamous, respiratory or transitional; it may contain mucus secreting cells and goblet cells
Variable koilocytosis may be present
Usually no / scant surface keratinization
Mitotic figures are absent or limited to the basal layer
Minimal inflammatory cells

Oncocytic papilloma:

Architecture: may have endophytic (inverted) or exophytic growth patterns
Epithelial lining is pseudostratified and columnar with abundant eosinophilic granular cytoplasm and hyperchromatic uniform nuclei
Intraepithelial mucin filled cysts with neutrophilic microabscesses may be seen

Malignant transformation (carcinoma ex sinonasal papilloma):

Most common type of carcinoma arising in sinonasal papilloma is squamous cell carcinoma
Other types of carcinoma that have been reported include verrucous carcinoma, mucoepidermoid carcinoma, small cell carcinoma and sinonasal undifferentiated carcinoma (Head Neck Pathol 2017;11:269)
Carcinoma is characterized by marked nuclear pleomorphism and hyperchromasia, frequent mitotic figures beyond basal layer including the atypical forms, tumor necrosis and frank invasion with infiltrative irregular nests and desmoplastic stromal reaction

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Inverted papilloma

Exophytic papilloma

Oncocytic papilloma

Malignant transformation (carcinoma ex sinonasal papilloma)

Positive stains

Cytokeratin AE1 / AE3, CK7, CK5 / 6 (in squamous lining), p40 (in squamous lining)

Negative stains

S100, CD45 and other nonepithelial markers

Molecular / cytogenetics description

Inverted papilloma may be positive for low risk or high risk HPV by in situ hybridization
Exophytic papilloma may be positive for low risk HPV by in situ hybridization
88% of inverted papilloma and 77% of carcinoma ex inverted papilloma harbor EGFR mutations (Cancer Res 2015;75:2600)
Most oncocytic papillomas, including those with malignant transformation, have KRAS mutations (J Pathol 2016;239:394)

Sample pathology report

Maxillary sinus, left; biopsy:
- Sinonasal papilloma, inverted type

Differential diagnosis

Cutaneous squamous papilloma:
- May involve nasal vestibule and become a differential diagnosis for exophytic papilloma
- May show surface keratinization
- Lacks mucocytes and ciliated respiratory epithelium
- May contain skin adnexa but lacks seromucinous glands
Nonintestinal type sinonasal adenocarcinoma:
- Has oncocytic cytomorphologic features and is a differential diagnosis for oncocytic papilloma
- Characterized by complex, confluent, back to back glandular proliferation, while oncocytic papilloma has a simple exophytic or endophytic growth pattern without architectural complexity
- High grade tumors may show marked nuclear atypia
Nonkeratinizing squamous cell carcinoma:
- Infiltrative growth, irregular border, marked nuclear atypia, frequent mitoses, desmoplastic reaction, unequivocal invasion and tumor necrosis
Respiratory epithelial adenomatoid hamartoma:
- Downward proliferation of respiratory mucosa can mimic inverted papilloma
- Surrounded by a thickened basement membrane
- Absence of hyperplastic changes in the epithelial lining
- Associated with an increase of seromucinous glands
Rhinosporidiosis:
- Endospores involving the submucosa that may mimic microcysts of oncocytic papilloma
- Endospores are located within stroma rather than epithelium
Sinonasal inflammatory polyp:
- Has epithelial lining commonly of respiratory type and lacks hyperplastic changes seen in sinonasal papilloma
- Lacks microcysts, transmigrating neutrophils and microabscesses seen in sinonasal papilloma

Additional references

Mod Pathol 2002;15:279

Board review style question #1

Which of the following statements about this sinonasal lesion is false?

Approximately 30% of cases are associated with high risk human papillomavirus (HPV)
It affects lateral nasal wall rather than nasal septum
It affects males and females equally
It carries approximately 10% risk of malignant transformation

Board review style answer #1

A. This is an oncocytic papilloma. It is not associated with HPV, so "Approximately 30% of cases are associated with high risk human papillomavirus (HPV)" is false.

Comment Here

Reference: Sinonasal papilloma

Board review style question #2

Which of the following statements about sinonasal papilloma is true?

Both inverted and oncocytic papilloma may show endophytic growth pattern
Oncocytic sinonasal papilloma has a negligible risk of malignant transformation
Standard of care for sinonasal papilloma is observation or excision for symptom control
Subtypes of papilloma that may be related to human papillomavirus (HPV) are oncocytic and exophytic subtypes; inverted papilloma has no significant association with HPV

Board review style answer #2

A. Both inverted and oncocytic papilloma may show endophytic growth pattern

Comment Here

Reference: Sinonasal papilloma

Sinonasal undifferentiated carcinoma

Table of Contents

Definition / general

WHO definition: undifferentiated carcinoma lacking evidence of differentiation (such as squamous, glandular or neuroendocrine differentiation) by histology and immunohistochemistry (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
Diagnosis of exclusion

Essential features

Undifferentiated carcinoma demonstrating epithelial differentiation but lacking specific squamous, glandular, neuroectodermal, mesenchymal, melanocytic or other lines of differentiation
Lacks specific viral etiologies, such as HPV and EBV
Lacks other specific genotypes, such as NUT (NUTM1) fusions, SWI/SNF deficiency and others (JNCI Cancer Spectr 2019;4:pkz094, Semin Diagn Pathol 2021;38:175, Hum Pathol 2020;104:105)
Lacks neuroendocrine differentiation that would justify for high grade neuroendocrine carcinoma, including large cell and small cell neuroendocrine carcinoma
Displays oncogenic IDH2 or IDH1 mutations in 80% of cases: IDH2 R172T is the most common mutation (Mod Pathol 2019;32:205, Am J Surg Pathol 2018;42:1067)

Terminology

Sinonasal undifferentiated carcinoma (SNUC)

ICD coding

ICD-10:
- C30.0 - malignant neoplasm of nasal cavity
- C31.1 - malignant neoplasm of ethmoid sinus

Epidemiology

Rare; 3 - 5% of all sinonasal carcinomas (Nat Rev Clin Oncol 2014;11:460)
Median age at presentation: 50 - 60 years (Curr Oncol Rep 2019;21:26)
Male predominance with M:F = 2 - 3:1 (Curr Oncol Rep 2019;21:26)
No clear clinical risk factors documented to date

Sites

Nasal cavity most common; may also affect paranasal sinus, such as ethmoid sinus and maxillary sinus (Am J Surg Pathol 2002;26:371)

Etiology

No consistent etiology has been reported

Clinical features

Presenting symptoms are variable, including nasal obstruction, epistaxis, facial pain and headache to severe visual symptoms (proptosis, diplopia and impaired visual acuity) and cranial nerve palsies (J Otolaryngol Head Neck Surg 2013;42:2)
Usually presents with stage 4 disease and involves the skull base and orbit (Curr Oncol Rep 2019;21:26)

Radiology images

Contributed by Bin Xu, M.D., Ph.D. and Abeer Salama, M.D.

MRI

Prognostic factors

Dismal prognosis
Overall, 5 and 10 year relative survival rates for SNUC patients were 34.9% and 31.3%, respectively (J Neurol Surg B Skull Base 2015;76:94)

Case reports

50 year old woman with SNUC of maxillary sinus metastasizing to the liver (Oncol Lett 2019;17:5811)
Man in his early to mid 50s with SNUC presenting with bilateral compressive optic neuropathy (JAMA Ophthalmol 2016;134:e155494)
60 year old man with a SNUC of maxillary sinus metastasizing to brain, lung and periaortic area (Autops Case Rep 2020;10:e2020222)
63 year old woman with SNUC arising in sinonasal inverted papilloma in the left maxillary sinus (Medicine (Baltimore) 2017;96:e8584)
80 year old man with SNUC arising in the left anterior nasal cavity involving the ethmoid, sphenoid and maxillary sinuses with brain metastasis (Cureus 2018;10:e2320)

Treatment

Multimodal therapy regimens incorporating intensified radiotherapy or chemotherapy after surgery (Head Neck 2017;39:1819)

Gross description

Usually > 4 cm
Tend to be fungating, with ill defined borders and frequent invasion into adjacent structures (Arch Pathol Lab Med 2009;133:699, Radiology 1997;202:477)

Microscopic (histologic) description

Nests, lobules, trabeculae and sheets of medium sized cells
Cells contain small amounts of eosinophilic cytoplasm, medium to large sized hyperchromatic to vesicular nuclei, inconspicuous to prominent nucleoli and poorly defined cell membrane
Mitotic activity is very high
Tumor necrosis and apoptoses are frequent
Lymphovascular invasion and perineural invasion are common
Lacks any definite lineage of differentiation
- Squamous differentiation (e.g. keratin pearls and intracellular bridges)
- Glandular differentiation (e.g. glandular lumen or acinar architecture)
- Neuroectodermal differentiation (e.g. neurofibrillary material and true neural rosettes)
Reference: Adv Anat Pathol 2020;27:51

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D. and Abeer Salama, M.D.

Lobules and sheets of malignant cells

Cytologic features of malignant epithelial cells

High grade features: mitosis and apoptosis

Cytokeratin AE1 / AE3

IDH2 R172T immunohistochemistry

Positive stains

Pancytokeratin AE1 / AE3, low molecular weight cytokeratin (CAM 5.2)
CK7: expressed in half of SNUC (Am J Surg Pathol 2002;26:1597)
Retain (i.e. no aberrant loss) of SWI/SNF complex, including SMARCB1 / INI1, SMARCA4 / BRG1 and SMARCA2 / BRM
IDH mutation protein such as IDH2 R172T can be detected by immunohistochemistry in 70% (Mod Pathol 2019;32:205, Am J Surg Pathol 2018;42:1067)

Negative stains

Minimal to absent expression of lineage markers, such as:
- Neuroendocrine markers: synaptophysin, chromogranin and INSM1 (Am J Surg Pathol 2001;25:156)
- Squamous markers: e.g. CK5/6, p63 and p40 (Ann Diagn Pathol 2014;18:261)
NUT
Negative for immunomarkers specific for sarcoma (e.g. CD99, desmin and myogenin), lymphoma (e.g. CD45), melanoma (e.g. MelanA and HMB45)

Molecular / cytogenetics description

IDH2 or IDH1 mutations in > 80% cases, the most common being IDH2 R172 mutation (Mod Pathol 2019;32:1447)
- IDH2 mutant large cell neuroendocrine carcinoma is genetically similar to the IDH2 mutant SNUC
In situ hybridization for high risk HPV and EBV is consistently negative

Sample pathology report

Nasal cavity, biopsy:
- Poorly differentiated carcinoma, most consistent with sinonasal undifferentiated carcinoma (SNUC), at least 1.15 cm in greatest dimension, invading bone (see comment)
- Comment: Immunohistochemical stains show that the tumor cells are focal staining of AE1 / AE3, Cam 5.2 and IDH2 R172S, while they are negative for CK5/6, synaptophysin, chromogranin, IDH1-R132H, calretinin, NUT, P40, S100 and calponin. The immunostaining for BAF47, BRM and BRG1 is retained in the tumor. In situ hybridization for high risk HPV and EBV (EBER) are negative in the tumor.

Differential diagnosis

Differential diagnoses of SNUC are broad and encompass a wide range of poorly differentiated carcinomas, sarcoma, melanoma and lymphoma
- Squamous cell carcinoma:
  - Shows squamous differentiation by histology (e.g. keratin pearls and intercellular bridges) or by immunohistochemistry (e.g. immunopositivity for p40 and CK5/6)
- Adenocarcinoma:
  - Shows glandular differentiation by histology
- High grade salivary gland carcinoma:
  - Shows histologic, immunohistochemical and molecular characteristics of salivary gland carcinoma
- High grade neuroendocrine carcinoma:
  - Large cell neuroendocrine carcinoma has coarse or specked chromatin, prominent nucleoli
  - Small cell undifferentiated neuroendocrine carcinoma has salt and pepper chromatin and nuclear molding
  - Nonfocal immunoexpression of neuroendocrine markers (e.g. synaptophysin, chromogranin and INSM1)
  - Like SNUC, might harbor IDH2 mutation
- Olfactory neuroblastoma:
  - Express neuroendocrine markers
  - Positive for S100 in a sustentacular pattern
  - Keratin expression is typically absent or focal (in less than 25% of cases)
- SWI/SNF deficient sinonasal carcinoma:
  - Mutation of SMARCB1, SMARCA2 or SMARCA4 detected by molecular testing or loss of immunoexpression of SMARCB1, SMARCA2 or SMARCA4 by immunohistochemistry
- NUT carcinoma:
  - Detection of NUT (NUTM1) fusion by molecular testing or abnormal diffuse speckled NUT nuclear immunopositivity by immunohistochemistry
- HPV related multiphenotypic sinonasal carcinoma:
  - Shows salivary / myoepithelial differentiation by histology
  - Positive for high risk HPV
- Sarcoma
- Melanoma:
  - MelanA, SOX10, S100 positive
- Lymphoma:
  - CD45 positive

Board review style question #1

Which of the following statement about sinonasal undifferentiated carcinoma (SNUC) is true?

20% of SNUC are positive for high risk HPV
It is a diagnosis of exclusion
It is commonly diffusely positive for synaptophysin
SMARCB1 (INI1) immunostain is lost in this tumor

Board review style answer #1

B. It is a diagnosis of exclusion. SNUC can be focally positive for neuroendocrine markers (e.g. synaptophysin). However, diffuse synaptophysin positivity hints towards olfactory neuroblastoma, paraganglioma or neuroendocrine neoplasm. SMARCB1 loss is characteristic for SMARCB1 deficient sinonasal carcinoma. SNUC has no association with high risk HPV. The correct answer is B (SNUC is a diagnosis of exclusion).

Comment Here

Reference: Sinonasal undifferentiated carcinoma

Board review style question #2

Which of the following sinonasal carcinoma harbors frequent IDH2 mutation?

Nasopharyngeal carcinoma
NUT carcinoma
Sinonasal undifferentiated carcinoma (SNUC)
SMARCA4 and SMARCB1 deficient carcinoma

Board review style answer #2

C. Sinonasal undifferentiated carcinoma (SNUC)

Comment Here

Reference: Sinonasal undifferentiated carcinoma

Squamous cell carcinoma

Table of Contents

Definition / general

Epithelial malignancy originating from sinonasal surface epithelium

Terminology

Two broad histologic subtypes: keratinizing and nonkeratinizing

Epidemiology

~3% of malignancies of head and neck; < 1% of malignant neoplasms at all sites
Most common malignant epithelial neoplasm of sinonasal tract
More common in Japan than in the West
More common in adult men
Average age at presentation is 55 - 65 years
Rare in patients < 40 years old

Sites

Maxillary sinus (60 - 70%), nasal cavity (12 - 25%), ethmoid sinus (10 - 15%), ethmoid and frontal sinuses (1%)

Etiology

Reported risk factors include exposure to nickel, chlorophenols, textile dust, thorotrast and smoking (Int J Otolaryngol 2013;2013:672621)
May develop from Schneiderian papilloma and be associated with HPV (Laryngoscope 2001;111:1104)

Clinical features

Nasal fullness, epistaxis, rhinorrhea, pain, nasal / facial swelling are common presentations
Advanced cases may present with proptosis, diplopia or lacrimation

Prognostic factors

Patients with nasal tumors usually present earlier and have better prognosis than those with maxillary sinus tumors
Overall 5 year survival of nasal squamous cell carcinoma is ~60% versus 42% for maxillary sinus tumor
Prognosis usually correlates with tumor stage (Arch Otolaryngol Head Neck Surg 2007;133:131)
Nonkeratinizing squamous cell carcinoma usually has better prognosis than keratinizing type

Case reports

60 and 85 year old patients with basaloid squamous cell carcinoma of maxillary sinus (Oncol Lett 2013;5:1755)

Treatment

Complete surgical resection and adjuvant radiotherapy

Gross description

Variegated appearance: exophytic, fungating or papillary; friable, hemorrhagic or necrotic mass

Microscopic (histologic) description

Two broad microscopic subtypes:
- Keratinizing squamous cell carcinoma:
  - 80 - 85% cases
  - Histologically identical to squamous cell carcinoma at other mucosal sites in head and neck; either well, moderately or poorly differentiated
- Nonkeratinizing (cylindrical cell / transitional) carcinoma
Morphologic variants:
- Adenosquamous carcinoma
- Basaloid squamous cell carcinoma
- Papillary squamous cell carcinoma
- Spindle cell carcinoma
- Verrucous carcinoma

Microscopic (histologic) images

Images hosted on other servers:

Keratinizing squamous cell carcinoma

Nonkeratinizing squamous cell carcinoma

Basaloid SCC: H&E and p63

Positive stains

CK5 / 6, CK8, CK13, CK14, CK19
CK7 (60%), CK4 (30%)

Differential diagnosis

Postchemotherapy changes
Scheinederian papillomas

Additional references

Mod Pathol 2002;15:229

Staging terminology

Table of Contents

Anatomy | Surgical margins | Extranodal extension (ENE) | TNM descriptors

Anatomy

Anatomic sites and subsites for the nasal cavity and paranasal sinuses
- Nasal cavity is divided in the midline to right and left halves by the septum; each half opens on the face via the nares or nostrils and communicates behind with the nasopharynx through the posterior nasal apertures or the choanae
  - Nasal cavity is divided into 4 subsites including the septum, floor, lateral wall and vestibule
  - Paranasal sinuses represent a grouping of 4 paired sinuses including the maxillary sinuses, ethmoid sinuses, frontal sinuses and sphenoid sinuses
  - Nasoethmoidal complex is divided into 2 sites including the nasal cavity and the ethmoid sinuses

Surgical margins

Surgical margins (AJCC: Cancer Staging [Accessed 3 December 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Nasal Cavity and Paranasal Sinuses [Accessed 3 December 2018]):
- Definition of a positive margin is somewhat controversial given the varied results from prior studies
  - This is made even more challenging and nebulous for sinonasal tumors, which are often received piecemeal with margins submitted separately
  - But for squamous cell carcinoma, data is essentially extrapolated from other sites
  - Here, overall, several studies support the definition of a positive margin to be invasive carcinoma or carcinoma in situ / high grade dysplasia present at margins (microscopic cut through of tumor)
  - Furthermore, reporting of surgical margins should also include information regarding the distance of invasive carcinoma, carcinoma in situ or high grade dysplasia (moderate to severe) from the surgical margin
- Tumors with "close" margins also carry an increased risk for local recurrence
  - Definition of a "close" margin is not standardized as the effective cutoff varies between studies and between anatomic subsites
  - Commonly used cutpoints to define close margins are 5 mm in general and 2 mm with respect to glottic larynx
  - However, values ranging from 3 to 7 mm have been used with success and for glottic tumors as low as 1 mm
  - Thus, distance of tumor from the nearest margin should be recorded
- Reporting of surgical margins for carcinomas of the minor salivary glands should follow those used for squamous cell carcinoma of oral cavity
- While there is no standard recommendation for the other histologic types of carcinoma encountered, adherence to the recommendations for squamous cell carcinoma is acceptable

Extranodal extension (ENE)

Extranodal extension (ENE) (AJCC: Cancer Staging [Accessed 3 December 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Nasal Cavity and Paranasal Sinuses [Accessed 3 December 2018]):
- 8th edition introduces the use of extranodal extension in categorizing the "N" category for metastatic cancer to neck nodes
- Effect of ENE on prognosis in head and neck cancers is profound, except for those tumors associated with HR HPV
- Pathological ENE also must be clearly defined as extension of metastatic tumor (tumor present within the confines of the lymph node and extending through the lymph node capsule into the surrounding connective tissue, with or without associated stromal reaction)
- Histopathologic designations for ENE are as follows (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018):
  - ENE_n (none)
  - ENE_mi (microscopic ENE ≤ 2 mm)
  - ENE_ma (ENE > 2 mm or gross ENE)
- ENE_mi and ENE_ma are used to define pathological ENE nodal status
- ENE_mi versus ENE_n will affect current nodal staging but data collection is recommended to allow standardization of data collection and future analysis (AJCC: Cancer Staging [Accessed 3 December 2018])

TNM descriptors

TNM descriptors:
- By AJCC / UICC convention, the designation "T" refers to a primary tumor that has not been previously treated
- "p" symbol refers to the pathologic classification of the TNM, as opposed to the clinical classification and based on clinical stage information supplemented / modified by operative findings and gross and microscopic evaluation of the resected specimens
- pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis and pM entails microscopic examination of distant lesions
- Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible
- Pathologic staging is usually performed after surgical resection of the primary tumor
  - Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed
  - If a biopsied tumor is not resected for any reason (e.g. when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer
- Use of pT0:
  - Additional change in AJCC 8th edition is the elimination of the T0 category for all oral cavity, skin, larynx, HPV- oropharynx, hypopharynx and sinus
  - This change affects cases where a cervical lymph node has metastatic squamous cell carcinoma but no primary tumor is identified despite thorough history, examination and available imaging studies
  - Assigning these cases to a specific head and neck site is not possible
  - Previous editions of TNM staging included a T0 category in each of these disease sites
  - However, it is seldom used and if it is, the cancer could not be assigned to a stage group
  - Therefore, for the 8th edition, the expert panel eliminated the T0 category from the head and neck staging systems
Additional TNM descriptors:
- For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y" and "r" prefixes are used; although they do not affect the stage grouping, they indicate cases needing separate analysis
- "m" suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM
- "y" prefix indicates those cases in which classification is performed during or following initial multimodality therapy (i.e. neoadjuvant chemotherapy, radiation therapy or both chemotherapy and radiation therapy)
- cTNM or pTNM category is identified by a "y" prefix
  - ycTNM or ypTNM categorize the extent of tumor actually present at the time of that examination
  - "y" categorization is not an estimate of tumor prior to multimodality therapy (i.e. before initiation of neoadjuvant therapy)
- "r" prefix indicates a recurrent tumor when staged after a documented disease free interval and is identified by the "r" prefix: rTNM

Staging-nasal cavity & sinuses

Table of Contents

Definition / general

Staging of definitive resections for carcinoma (squamous cell carcinoma, neuroendocrine carcinoma and minor salivary gland carcinoma) of the nasal cavity and paranasal sinuses should use this system (AJCC: Cancer Staging [Accessed 24 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Nasal Cavity and Paranasal Sinuses [Accessed 24 September 2018])
Cancer of the maxillary sinus is the most common of the sinonasal malignancies
- Ethmoid sinus and nasal cavity cancers are equal in frequency but considerably less common than maxillary sinus cancers
- Tumors of the sphenoid and frontal sinuses are rare
Staging protocols such as those of CAP are to document procedure, tumor site, tumor laterality, tumor focality, tumor size, histologic type, histologic grade where applicable, margin status, lymphovascular invasion, perineural invasion, regional lymph node findings and summarize these pathologic findings using TNM system

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory
Use of the CAP protocol is not required for recurrent tumors or for metastatic tumors that are resected at a different time than the primary tumor
- Use of this protocol is also not required for pathology reviews performed at a second institution (i.e. secondary consultation, second opinion or review of outside case at second institution)
Reporting of surgical margins for carcinomas of the minor salivary glands should follow those used for squamous cell carcinoma
CAP staging protocol: CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Nasal Cavity and Paranasal Sinuses [Accessed 24 September 2018]
Alternatively for providers practicing in different geographic regions, there may be interest in the International Collaboration on Cancer Reporting (ICCR) guidelines: ICCR: Carcinomas of the Nasal Cavity and Paranasal Sinuses (TNM8) [Accessed 24 September 2018]

ICD coding

ICD-10:
- C30.0 - nasal cavity
- C31.0 - maxillary sinus
- C31.1 - ethmoid sinus

Clinical features

Cancers of the maxillary sinuses are the most common sinonasal malignancies, followed by cancers of the ethmoid sinuses, which are much less common
- Cancers of the frontal and sphenoid sinuses are rare
- When considering the nasal cavity and paranasal sinuses, 60% of malignant neoplasms originate from the maxillary sinus, 20 - 30% from the nasal cavity, 10 - 15% from the ethmoid sinus and 1% from the sphenoid and frontal sinuses
- When only considering the paranasal sinuses, 77% of malignant neoplasms originate from the maxillary sinus, 22% from the ethmoid sinus and 1% from the sphenoid and frontal sinuses
Location as well as the extent of the mucosal lesion in the maxillary sinus has prognostic importance
- Ohngren's line, connecting the medial canthus of the eye to the angle of the mandible, divides the maxillary sinus into an anterioinferior portion (infrastructure) and superioposterior portion (suprastructure) structures
- Carcinomas of the infrastructure are associated with a good prognosis; carcinomas of the suprastructure are associated with a poor prognosis
- Poorer prognosis with carcinomas of the suprastructure reflects early access of these tumors to critical structures, including the eye, skull base, pterygoids and infratemporal fossa (AJCC: Cancer Staging [Accessed 24 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Nasal Cavity and Paranasal Sinuses [Accessed 24 September 2018])

Primary tumor (pT) - maxillary sinus

pTX: Primary tumor cannot be assessed
pTis: Carcinoma in situ
pT1: Tumor limited to maxillary sinus mucosa with no erosion or destruction of bone
pT2: Tumor causing bone erosion or destruction including extension into the hard palate or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates
pT3: Tumor invades any of the following:
- Bone of the posterior wall of maxillary sinus
- Subcutaneous tissues
- Floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses
pT4: Moderately advanced or very advanced local disease
- pT4a: Moderately advanced local disease; tumor invades any of the following:
  - Anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses
- pT4b: Very advanced local disease; tumor invades any of the following:
  - Orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx or clivus

Primary tumor (pT) - nasal cavity and ethmoid sinus

pTX: Primary tumor cannot be assessed
pTis: Carcinoma in situ
pT1: Tumor restricted to any 1 subsite, with or without bone invasion
pT2: Tumor invading 2 subsites in a single region or extending to involve an adjacent region within the nasoethmoidal complex, with or without bone invasion
pT3: Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate or cribriform plate
pT4: Moderately advanced or very advanced local disease
- pT4a: Moderately advanced local disease; tumor invades any of the following:
  - Anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses
- pT4b: Very advanced local disease; tumor invades any of the following:
  - Orbital apex, dura, brain, middle cranial

Pathological regional lymph nodes (pN)

pNX: Regional lymph nodes cannot be assessed
pN0: No regional lymph node metastasis
pN1: Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension and extranodal extension negative (ENE-)
pN2a: Metastasis in:
- Single ipsilateral lymph node that is ≤ 3 cm and ENE+ or
- Single ipsilateral lymph node that is > 3 cm but ≤ 6 cm in greatest dimension and ENE-
pN2b: Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and ENE-
pN2c: Metastasis in bilateral or contralateral lymph node(s), none > 6 cm in greatest dimension and ENE-
pN3a: Metastasis in a lymph node that is > 6 cm in greatest dimension and ENE-
pN3b: Metastasis in:
- Single ipsilateral lymph node, > 3 cm and ENE+ or
- Multiple ipsilateral, contralateral or bilateral lymph nodes, any with ENE+ or
- Single contralateral lymph node of any size and ENE+

Notes:

Designation of "U" or "L" may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L)
A selective neck dissection will ordinarily include 10+ lymph nodes and a comprehensive neck dissection (radical or modified radical neck dissection) will ordinarily include 15+ lymph nodes
Negative pathologic examination of a smaller number of nodes still mandates a pN0 designation
Midline nodes are considered ipsilateral nodes

Distant metastasis (pM)

pM0: No distant metastasis
pM1: Distant metastasis

Notes:

Measurement of tumor metastasis (AJCC: Cancer Staging [Accessed 24 September 2018], CAP: Protocol for the Examination of Specimens from Patients with Cancers of the Nasal Cavity and Paranasal Sinuses [Accessed 24 September 2018]):
- Cross sectional diameter of the largest lymph node metastasis (not the lymph node itself) is measured in the gross specimen at the time of macroscopic examination or if necessary, on the histologic slide at the time of microscopic examination
- Measurement of the metastatic focus in the lymph nodes is based on the largest metastatic deposit size, which may include matted or fused lymph nodes

AJCC prognostic stage grouping

Stage 0:	Tis	N0	M0
Stage I:	T1	N0	M0
Stage II:	T2	N0	M0
Stage III:	T3	N0	M0
	T1 - 3	N1	M0
Stage IVA:	T4a	N0 - 1	M0
	T1 - 4a	N2	M0
Stage IVB:	Any T	N3	M0
	T4b	Any N	M0
Stage IVC:	Any T	Any N	M1

Registry data collection variables

Extranodal extension (ENE) clinical (present versus absent)
ENE pathological (present versus absent)
Extent of microscopic ENE (distance of extension from the native lymph node capsule to the farthest point of invasion in extranodal tissue)
Perineural invasion
Lymphovascular invasion
Performance status
Tobacco use and pack years
Alcohol use
Depression diagnosis

Histologic grade

GX: Cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated

Notes:

For histologic types of carcinomas that are amenable to grading, 3 histologic grades are suggested, as shown above
- For conventional squamous cell carcinoma, histologic grading as a whole does not perform well as a prognosticator
- Nonetheless, it should be recorded when applicable, as it is a basic tumor characteristic
- Selecting either the most prevalent grade or the highest grade for this synoptic protocol is acceptable
- Variants of squamous cell carcinoma (i.e. verrucous, basaloid, etc.) have an intrinsic biologic potential and currently do not appear to require grading
Histologic (microscopic) grading of salivary gland carcinomas has been shown to be an independent predictor of behavior and plays a role in optimizing therapy
- However, most salivary gland carcinoma types have an intrinsic biologic behavior and attempted application of a universal grading scheme is merely a crude surrogate
- Thus a generic grading scheme is no longer recommended for salivary gland carcinomas
- Carcinoma types for which grading systems exist and are relevant are incorporated into histologic type
- 3 major categories that are amenable to grading include adenoid cystic carcinoma, mucoepidermoid carcinoma and adenocarcinoma, not otherwise specified
In some carcinomas, histologic grading may be based on growth pattern, such as in adenoid cystic carcinoma, for which a histologic high grade variant has been recognized based on the percentage of solid growth
- Those adenoid cystic carcinomas showing ≥ 30% of solid growth pattern are considered to be histologically high grade carcinomas
- Histologic grading of mucoepidermoid carcinoma includes a combination of growth pattern characteristics (e.g. cystic, solid, neurotropism) and cytomorphologic findings (e.g. anaplasia, mitoses, necrosis)
- Adenocarcinomas, not otherwise specified do not have a formalized grading scheme and are graded intuitively based on cytomorphologic features
For nonsalivary sinonasal adenocarcinoma, intestinal type adenocarcinoma grading is based on growth pattern
- Generally, papillary patterns correspond to low grade tumors, colonic to intermediate grade and solid to high grade
- Mucinous and mixed types have variable behavior
- Nonintestinal type adenocarcinomas are graded intuitively into low, intermediate and high grade tumors

Histologic type

CAP protocol applies only to carcinomas and melanomas and does not apply to lymphomas, sarcomas or neuroectodermal tumors (e.g. olfactory neuroblastoma, primitive neuroectodermal tumor [PNET], others)
Nasal cavity and paranasal sinuses
- Squamous cell carcinoma, keratinizing
- Squamous cell carcinoma, nonkeratinizing
- Adenosquamous carcinoma
- Basaloid squamous cell carcinoma
- Papillary squamous cell carcinoma
- Spindle cell squamous cell carcinoma
- Verrucous squamous cell carcinoma
- Lymphoepithelial carcinoma (nonnasopharyngeal)
- Sinonasal undifferentiated carcinoma (SNUC)
- NUT carcinoma
Adenocarcinoma, non salivary gland type
- Intestinal type
- Nonintestinal type
Carcinomas of minor salivary glands
- Mucoepidermoid carcinoma, low grade
- Adenoid cystic carcinoma
- Acinic cell carcinoma
- Polymorphous adenocarcinoma
- (Mammary analogue) secretory carcinoma
- Salivary duct carcinoma
- Carcinoma ex pleomorphic adenoma
- Epithelial myoepithelial carcinoma
- (Hyalinizing) clear cell carcinoma
- Adenocarcinoma, not otherwise specified
Neuroendocrine carcinoma
- Large cell neuroendocrine carcinoma
- Small cell neuroendocrine carcinoma

Board review style question #1

Based on the gross and microscopic examination of the 2.2 cm nasal cavity adenosquamous carcinoma originating along the right nasal septum in the following images, which of the pT category criteria in the 8th edition AJCC staging guide is satisfied?

Image 1

Image 2

Image 3

Image 4

pT1 due to tumor size
pT2 due to tumor size
pT3 due to extension to overlying nasal skin
pT4 due to extension to overlying nasal skin

Board review style answer #1

D. pT4 due to extension to overlying nasal skin

Comment Here

Reference: Pathologic TNM staging of nasal cavity and paranasal sinuses (AJCC 8th edition)

Staging-nasopharynx

Table of Contents

Definition / general

All primary carcinomas of the nasopharynx are covered by this staging system
These topics are not covered: metastasis, mucosal melanoma, lymphoma and sarcoma

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory

ICD coding

ICD-O:
- 8071/3 - keratinizing squamous cell carcinoma
- 8072/3 - nonkeratinizing squamous cell carcinoma
- 8083/3 - basaloid squamous cell carcinoma
- 8260/3 - nasopharyngeal papillary adenocarcinoma
- 8200/3 - salivary gland carcinoma

Primary tumor (pT)

pTX: cannot be assessed
pT0: no evidence of primary tumor, with proven EBV positive lymph node metastasis
pTis: carcinoma in situ
pT1: confined to nasopharynx or involvement to oropharynx or nasal cavity without parapharyngeal extension
pT2: parapharyngeal extension or involvement of adjacent soft tissue including medial pterygoid / lateral pterygoid / prevertebral muscles
pT3: bone invasion into skull base, cervical vertebra, pterygoid structures or paranasal sinuses
pT4: involvement of intracranial structures, cranial nerve, hypopharynx, orbit or parotid gland or invasion beyond the lateral surface of the lateral pterygoid muscle

Regional lymph nodes (pN)

pNX: cannot be assessed
pN0: no regional lymph node metastasis
pN1: metastasis to unilateral cervical lymph node(s) or unilateral / bilateral retropharyngeal lymph node(s), above the inferior border of cricoid cartilage, ≤ 6 cm in size
pN2: metastasis to bilateral cervical lymph nodes, above the inferior border of cricoid cartilage, ≤ 6 cm in size
pN3: metastasis > 6 cm in size or below the inferior border of cricoid cartilage

Distant metastasis (pM)

pM1: distant metastasis

Prefixes

y: preoperative radiotherapy or chemotherapy
r: recurrent tumor stage

AJCC prognostic stage groups

Stage group 0:	Tis	N0	M0
Stage group I:	T1	N0	M0
Stage group II:	T0 or T1	N1	M0
	T2	N0 or N1	M0
Stage group III:	T0, T1 or T2	N2	M0
	T3	N0, N1 or N2	M0
Stage group IV:	T4	any N	any M
	any T	N3	any M
	any T	any N	M1
Stage group IVA:	T4	any N	M0
	any T	N3	M0
Stage group IVB:	any T	any N	M1

Registry data collection variables

Not applicable

Histologic grade (G)

Not applicable for nasopharyngeal carcinoma

Histopathologic type

Nasopharyngeal carcinoma
- Keratinizing squamous cell carcinoma
- Nonkeratinizing squamous cell carcinoma
- Basaloid squamous cell carcinoma
Nasopharyngeal papillary adenocarcinoma
Salivary gland carcinoma

Board review style question #1

Which of the following statements about the AJCC staging (8th edition) for nasopharyngeal carcinoma is true?

pN is determined using a combination of laterality and location of involved lymph node and size of the metastasis
The presence of extranodal extension increases the pN category
pT is determined by tumor size and site of involvement
A cervical lymph node with EBV positive squamous cell carcinoma and no primary tumor detected after extensive sampling is pTX

Board review style answer #1

A. pN is determined using a combination of laterality and location of involved lymph node and size of the metastasis

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Reference: Pathologic TNM staging of nasopharynx (AJCC 8th edition)

SWI / SNF complex deficient sinonasal carcinoma

Table of Contents

Definition / general

Aggressive carcinoma defined by SMARCB1 gene mutations and associated loss of immunohistochemical expression
Provisional entity in El-Naggar: WHO Classification of Head and Neck Tumors, 4th Edition, 2017

Essential features

Sinonasal carcinoma defined by inactivation of SMARCB1 gene
Loss of SMARCB1 (INI1) immunohistochemical expression is highly sensitive and specific for diagnosis in this site
Tumors are high grade but demonstrate cytological uniformity
Tumors have variable proportions of basaloid and rhabdoid / plasmacytoid cells
Highly aggressive clinical behavior

Terminology

SMARCB1 stands for SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1
The protein product of the SMARCB1 gene is also sometimes known as INI1, which stands for integrase interactor 1

ICD coding

ICD-10:
- C30.0 - malignant neoplasm of nasal cavity
- C31.1 - malignant neoplasm of ethmoidal sinus

Epidemiology

Described in patients from 16 to 89 years old (Virchows Arch 2015;467:649, Pathol Res Pract 2017;213:133)
M:F = 3:2 (Am J Surg Pathol 2017;41:458)
No clear clinical risk factors documented to date

Sites

Exclusively occurs in sinonasal tract
Most commonly arises in nasal cavity or ethmoid sinus but frequently involves multiple sites (Am J Surg Pathol 2017;41:458)

Clinical features

Most present with symptoms of mass effect such as nasal obstruction, headache, epistaxis, proptosis or visual deficits (Am J Surg Pathol 2017;41:458)
More than 80% present with stage T4 disease with bone, skull base or periorbital invasion

Radiology description

Avid contrast enhancement with intermediate to low T2 signal and fluorodeoxyglucose (FDG) avidity
Frequent calcification with occasional hair on end periosteal reaction (Am J Surg Pathol 2014;38:1274)

Radiology images

Images hosted on other servers:

Infiltration into orbit

Case reports

44 year old woman with tumor showing yolk sac differentiation (Int J Surg Pathol 2018;26:245)
53 year old man with highly necrotic tumor (Ann Otol Rhinol Laryngol 2019;128:676)
53 year old man with endobronchial metastases (Acta Cytol 2019 May 27 [Epub ahead of print])
61 year old woman with orbital compartment syndrome (Surv Ophthalmol 2019 Apr 10 [Epub ahead of print])
77 year old man with retropharyngeal lymph node metastasis (Diagn Cytopathol 2016;44:700)

Treatment

Best outcomes with trimodality therapy including surgical resection, external beam radiation and systemic chemotherapy (Head Neck Pathol 2017;11:256, Am J Surg Pathol 2017;41:458)

Gross description

Highly infiltrative tumor that frequently invades multiple sinonasal sites (Head Neck Pathol 2017;11:256)

Microscopic (histologic) description

Although tumors show high grade histologic features including prominent necrosis and mitoses, cytology is relatively uniform
Nuclei are round to oval with smooth nuclear contours
Two common morphologic variants: plasmacytoid / rhabdoid (40% of cases) and basaloid (60% of cases) (Am J Surg Pathol 2017;41:458)
Plasmacytoid / rhabdoid variant composed entirely of sheets of plasmacytoid / rhabdoid cells with abundant eosinophilic cytoplasm and eccentric nuclei
Basaloid variant composed of nests and lobules of basaloid cells with high nuclear cytoplasmic ratio and peripheral palisading and scattered plasmacytoid / rhabdoid cells
No overt squamous differentiation should be identified (Am J Surg Pathol 2014;38:1282)
Frequent formation of nonspecific vacuoles and occasional overt glandular differentiation (Hum Pathol 2019;83:59)
Subset shows papillary / exophytic growth (Virchows Arch 2015;467:649)
No associated surface dysplasia but pagetoid spread in overlying epithelium can be seen (Am J Surg Pathol 2014;38:1274)

Microscopic (histologic) images

Contributed by Lisa Rooper, M.D.

Highly infiltrative growth

Cytologic uniformity despite high grade

Nests of basaloid cells

Interspersed
basaloid and
rhabdoid
plasmacytoid cells

Sheets of rhabdoid plasmacytoid cells

No surface dysplasia

Cytoplasmic vacuoles

Loss of SMARCB1 (INI1)

Cytology description

Hypercellular smears with clusters of cohesive polygonal cells
Variable proportion of individual rhabdoid / plasmacytoid cells with abundant cytoplasm
Uniform nuclei with fine chromatin and small nucleoli
No overt keratinization or other evidence of squamous differentiation (Diagn Cytopathol 2016;44:700)
Apoptotic bodies common with abundant background necrotic debris (Cancer Cytopathol 2018;126:567)

Positive stains

Virtually always diffusely positive for pancytokeratin
Squamous markers p63 / p40 positive in > 50% of cases
Neuroendocrine markers synaptophysin / chromogranin positive in 30% of cases
Small subset of cases express diffuse p16 (Am J Surg Pathol 2017;41:458)

Negative stains

Defined by loss of SMARCB1 (INI1) expression with retained positivity in stroma
Myoepithelial markers such as S100, SMA and calponin are usually negative
Consistently negative for CD99 / NKX2.2 and NUT1

Molecular / cytogenetics description

Defined by inactivating mutations of SMARCB1 gene, a tumor suppressor gene located on chromosome 22q11.2 (Am J Surg Pathol 2014;38:1274, Am J Surg Pathol 2014;38:1282)
FISH less sensitive for diagnosis than immunohistochemistry, likely due to heterozygous deletions
Next generation sequencing has not identified other driver mutations within the limited number of cases evaluated (Pathol Res Pract 2017;213:133)
In situ hybridization for high risk HPV and EBV is consistently negative (Am J Surg Pathol 2017;41:458)

Sample pathology report

Nasal mass, biopsy:
- SMARCB1 deficient sinonasal carcinoma (see comment)
- Comment: Immunostains show that the tumor cells are positive for AE1/AE3 and p40, focally positive for synaptophysin and INSM1 and negative for NUT1, CD99, p16, S100 and calponin with loss of SMARCB1 (INI1) expression. SMARCB1 deficient sinonasal carcinoma is an aggressive tumor unique to the sinonasal tract that is defined by loss of SMARCB1 (INI1) expression (Am J Surg Pathol 2017;41:458).

Differential diagnosis

Sinonasal undifferentiated carcinoma:
- Also high grade but shows more prominent cytologic atypia and lacks rhabdoid / plasmacytoid cells
- Negative for p63 / p40 and synaptophysin / chromogranin with frequent IDH2 mutations
NUT carcinoma:
- Also high grade and frequently positive for p63 / p40
- Shows abrupt keratinization and positivity for NUT1 with retained SMARCB1 (INI1)
Myoepithelial carcinoma:
- Also demonstrates rhabdoid / plasmacytoid morphology and a subset show loss of SMARCB1 (INI1)
- Positive for myoepithelial markers S100, SMA and calponin
Adamantinoma-like Ewing sarcoma:
- Also high grade and frequently positive for p63 / p40 and synaptophysin / chromogranin
- Positive for CD99 / NKX2.1 with retained SMARCB1 (INI1)
High grade neuroendocrine carcinoma:
- Also high grade and positive for synaptophysin / chromogranin
- Speckled chromatin and retained SMARCB1 (INI1)
HPV related multiphenotypic sinonasal carcinoma:
- Also high grade with basaloid features and positivity for p63 / p40
- Distinct biphasic basal and ductal populations, positive for HPV and retained SMARCB1 (INI1)

Board review style question #1

A 30 year old man presented with a destructive sinonasal tumor. Biopsy findings are shown in the photomicrograph above. What molecular alteration is thought to be the driver of this tumor?

Mutations in IDH2
EWSR1 translocations
NUT1 translocations
Inactivation of SMARCB1

Board review style answer #1

D. Inactivation of SMARCB1. This photomicrograph depicts a SMARCB1 deficient sinonasal carcinoma, an aggressive sinonasal tumor that is defined by genetic inactivation of the SMARCB1 gene with corresponding immunohistochemical loss of SMARCB1 (INI1) protein expression. The other genetic abnormalities listed here are characteristic of other high grade sinonasal tumors that fall into the differential diagnosis of SMARCB1 deficient sinonasal carcinoma, including IDH2 mutations in sinonasal undifferentiated carcinoma, EWSR1 translocation in adamantinoma-like Ewing sarcoma and NUT1 translocation in NUT carcinoma; these other tumor types all demonstrate retained immunohistochemical expression of SMARCB1.

Comment here

Reference: SMARCB1 deficient sinonasal carcinoma

Board review style question #2

What feature would essentially exclude the diagnosis of SMARCB1 deficient sinonasal carcinoma?

Basaloid cell nests with peripheral palisading and strong p40 positivity
Diffuse positivity for p16 immunohistochemistry and high risk HPV RNA in situ hybridization
Formation of glandular lumina with mucin production
Retained SMARCB1 signals by FISH

Board review style answer #2

B. Diffuse positivity for p16 immunohistochemistry and high risk HPV RNA in situ hybridization. SMARCB1 deficient sinonasal carcinoma can show a variety of morphologic features and a highly variable immunohistochemical profile. Histologically, SMARCB1 deficient sinonasal carcinoma is composed of various proportions of basaloid and plasmacytoid / rhabdoid cells; a subset of cases can show glandular differentiation. The most sensitive and specific feature for diagnosis is consistent loss of SMARCB1 (INI1) expression by immunohistochemistry; while FISH generally shows loss as well, signals can be retained in rare cases due to heterozygous mutations. Otherwise SMARCB1 deficient sinonasal carcinoma is immunohistochemically heterogeneous with variable positivity for p63 / p40 and synaptophysin / chromogranin; a subset of cases can even demonstrate diffuse p16 positivity. However, in situ hybridization for high risk HPV should be consistently negative.

Comment here

Reference: SMARCB1 deficient sinonasal carcinoma

Teratocarcinosarcoma

Table of Contents

Definition / general

Features of carcinosarcoma and immature teratoma
Adults; poor prognosis with 3 year survival of 40% due to uncontrollable local growth

Terminology

Also known as teratoid carcinosarcoma

Microscopic (histologic) description

Primitive neuroepithelial elements with well formed rosettes
Well formed glands with atypical epithelium
Myxoid tissue
Rhabdomyosarcomatous differentiation
Benign and malignant cartilage
Cellular areas

Positive stains

CD99, NSE, vimentin, keratin, EMA, GFAP, chromogranin, synaptophysin

Negative stains

Beta hCG, CD45 / LCA

Additional references

Hum Pathol 1998;29:718

WHO classification

Table of Contents

Definition / general

Classification is based on WHO classification of tumors of the nasal cavity, paranasal sinuses and skull base (4th edition, 2017)

Major updates

Several new entities and provisional entities were added to the chapter of nasal cavity, paranasal sinuses and skull base, including:
- HPV related multiphenotypic sinonasal carcinoma
- SMARCB1 deficient sinonasal carcinoma
- Renal cell-like adenocarcinoma
- Seromucinous hamartoma
- NUT carcinoma
- Biphenotypic sinonasal sarcoma

WHO (2017) nasal cavity, paranasal sinuses and skull base

Carcinomas

ICD-O codes

Keratinizing squamous cell carcinoma 8071/3
Nonkeratinizing squamous cell carcinoma 8072/3
- Provisional entity: HPV related multiphenotypic sinonasal carcinoma
Spindle cell squamous cell carcinoma 8074/3
Lymphoepithelial carcinoma 8082/3
Sinonasal undifferentiated carcinoma 8020/3
- Provisional entity: SMARCB1 deficient sinonasal carcinoma
NUT carcinoma 8023/3
Neuroendocrine carcinoma
- Small cell neuroendocrine carcinoma 8041/3
- Large cell neuroendocrine carcinoma 8013/3
Adenocarcinoma
- Intestinal type adenocarcinoma 8144/3
- Nonintestinal type adenocarcinoma 8140/3
- Provisional entity: renal cell-like adenocarcinoma

Teratocarcinosarcoma

9081/3

Sinonasal papillomas

ICD-O codes

Sinonasal papilloma, inverted type 8121/1
Sinonasal papilloma, oncocytic type 8121/1
Sinonasal papilloma, exophytic type 8121/0

Respiratory epithelial lesions

Salivary gland tumors

ICD-O codes

Pleomorphic adenoma 8940/0

Malignant soft tissue tumors

ICD-O codes

Fibrosarcoma 8810/3
Undifferentiated pleomorphic sarcoma 8802/3
Leiomyosarcoma 8890/3
Rhabdomyosarcoma, NOS 8900/3
Embryonal rhabdomyosarcoma 8910/3
Alveolar rhabdomyosarcoma 8920/3
Pleomorphic rhabdomyosarcoma, adult type 8901/3
Spindle cell rhabdomyosarcoma 8912/3
Angiosarcoma 9120/3
Malignant peripheral nerve sheath tumor 9540/3
Biphenotypic sinonasal sarcoma
Synovial sarcoma 9040/3

Borderline / low grade malignant soft tissue tumors

ICD-O codes

Benign soft tissue tumors

ICD-O codes

Leiomyoma 8890/0
Hemangioma 9120/0
Schwannoma 9560/0
Neurofibroma 9540/0

Other tumors

ICD-O codes

Meningioma 9530/0
Sinonasal ameloblastoma 9310/0
Chondromesenchymal hamartoma

Hematolymphoid tumors

ICD-O codes

Extranodal NK / T cell lymphoma 9719/3
Extraosseous plasmacytoma 9734/3

Neuroectodermal / melanocytic tumors

ICD-O codes

Ewing sarcoma / primitive neuroectodermal tumor (PNET) 9364/3
Olfactory neuroblastoma 9522/3
Mucosal melanoma 8720/3

WHO (2017) nasopharynx

Nasopharyngeal carcinoma

ICD-O codes

Nonkeratinizing squamous cell carcinoma 8072/3
Keratinizing squamous cell carcinoma 8071/3
Basaloid squamous cell carcinoma 8083/3

Nasopharyngeal papillary adenocarcinoma

8260/3

Salivary gland tumors

ICD-O codes

Adenoid cystic carcinoma 8200/3
Salivary gland anlage tumor

Benign and borderline lesions

ICD-O codes

Hairy polyp
Ectopic pituitary adenoma 8272/0
Craniopharyngioma 9350/1

Soft tissue tumors

ICD-O codes

Nasopharyngeal angiofibroma 9160/0

Hematolymphoid tumors

ICD-O codes

Diffuse large B cell lymphoma 9680/3
Extraosseous plasmacytoma 9734/3
Extramedullary myeloid sarcoma 9930/3

Notochord tumors

ICD-O codes

Chordoma 9370/3

Videos

WHO's new in sinonasal tract pathology
Dr. Thompson

Additional references

El-Naggar: WHO Classfication of Head and Neck Tumours, 4th Edition, 2017, Head Neck Pathol 2017;11:16, Head Neck Pathol 2017;11:3, Virchows Arch 2018;472:315

Board review style question #1

What are the three subtypes of nasopharyngeal carcinoma in the WHO classification?

Keratinizing, nonkeratinizing, basaloid
Keratinizing, nonkeratinizing, neuroendocrine carcinoma
Keratinizing, nonkeratinizing, nasopharyngeal papillary adenocarcinoma
Keratinizing, nonkeratinizing, HPV-positive

Board review style answer #1

A. Keratinizing, nonkeratinizing, basaloid

Comment Here

Reference: WHO classification

Recent Nasal cavity, paranasal sinuses, nasopharynx Pathology books

Cardesa: 2016

Franchi: 2020

Gnepp: 2021

IARC: 2024

Neville: 2023

Robinson: 2012

Stelow: 2020

Thompson: 2022

Volavsek: 2016

Wenig: 2017

Wenig: 2024

Find related Pathology books: head & neck/endocrine

Home > Nasal cavity, paranasal sinuses, nasopharynx

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