Head and Neck Pathology (2021) 15:120–129

https://doi.org/10.1007/s12105-020-01272-7

PROCEEDINGS OF THE NORTH AMERICAN SOCIETY OF HEAD AND NECK

PATHOLOGY, BALTIMORE, MD, MARCH 17, 2021

Algorithmic Approach to Fibroinflammatory Sinonasal Tract Lesions

Lester D. R. Thompson1

Received: 30 November 2020 / Revised: 8 December 2020 / Accepted: 10 December 2020 / Published online: 15 March 2021
© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021

Abstract
Fibroinflammatory lesions of the sinonasal tract are one of the most common head and neck lesions submitted to surgical
pathology. When the fibroinflammatory pattern represents the lesion (i.e., not surface reactive ulceration), an algorithmic
approach can be useful. Separated into reactive, infectious, and neoplastic, and then further divided based on common to
rare, this logical progression through a series of differential considerations allows for many of these lesions to be correctly
diagnosed. The reactive lesions include chronic rhinosinusitis and polyps, granulomatosis with polyangiitis, and eosinophilic
angiocentric fibrosis. Infectious etiologies include acute invasive fungal rhinosinusitis, rhinoscleroma, and mycobacterial
infections. The neoplastic category includes lobular capillary hemangioma, inflammatory myofibroblastic tumor, and NK/T-
cell lymphoma, nasal type. Utilizing patterns of growth, dominant cell types, and additional histologic features, selected
ancillary studies help to confirm the diagnosis, guiding further clinical management.

Keywords Sinonasal tract · Fibroinflammatory lesions · Eosinophilic angiocentric fibrosis · Granulomatosis with
polyangiitis · Chronic rhinosinusitis · Mycobacterial pseudotumor · Rhinoscleroma · Differential diagnosis

Introduction common to rare, this logical progression through a series of

differential considerations (Fig. 1) allows for many of these
Fibroinflammatory lesions of the sinonasal tract are one of lesions to be correctly diagnosed.
the most common head and neck lesions submitted to surgi-
cal pathology. The majority represent the findings of chronic
rhinosinusitis and inflammatory polyps. However, within the Case Presentation
fibroinflammatory pattern, several distinct entities must be
considered as management and outcome are quite different A 35-year-old woman presented with worsening nasal
and unique. When the wrong diagnosis is made, surgical obstruction. There was some tenderness and swelling involv-
management versus supportive versus antimicrobial treat- ing the nares. There was no history of asthma, although she
ment results in an untoward outcome. An approach to such had reported allergies. By endoscopy, there was a firm, sym-
lesions is first to recognize that there is a mixed inflamma- metric swelling without normal cartilage mobility. The nasal
tory infiltrate associated with a background of spindled cells. airway was obstructed. By imaging, there was occlusion of
While surface ulceration over squamous cell carcinoma and the anterior-most airway at the level of the vestibule and
other spindled cell neoplasms must be excluded, it is when inferior turbinate, right sided more than the left. Laboratory
the fibroinflammatory pattern represents the lesion that an studies had not been performed. This was her third biopsy
algorithmic approach can be useful. Separated into reactive, in 2 years, with the first two samples called “chronic rhi-
infectious, and neoplastic, and then further divided based on nosinusitis.” Histologically, there was only lesional tissue
(Fig. 2a). The inflammatory infiltrate was comprised of a
full spectrum of cells, including lymphocytes, plasma cells,
* Lester D. R. Thompson
[email protected]
histiocytes, and acute inflammatory cells, with easily iden-
tified eosinophils (Fig. 2b). The inflammatory component
1
Department of Pathology, Southern California Permanente was identified around the walls of a number of vessels, but
Medical Group, 5601 De Soto Avenue, Woodland Hills, a true vasculitis was not identified: there was no fibrinoid
CA 91365, USA

13
Vol:.(1234567890)
Head and Neck Pathology (2021) 15:120–129 121

Fig. 1  A representation of several major categories to consider in the evaluation of sinonasal tract fibroinflammatory lesions

there was a concentric “onion-skin” whorling of the colla-

gen around the vessels (Fig. 2c). Biocollagenolytic necrosis
was not seen. Special studies for fungal and AFB organisms
were negative. The plasma cell population was polytypic
for kappa and lambda, with a mixture of B- and T-cells. No
polarizable foreign body material was present. Not wanting
to render a “nonspecific” diagnosis, the case was submitted
for consultation hoping to obtain a more definitive diagno-
sis. IgG and ­IgG4 immunohistochemistry demonstrated > 50
­IgG4-positive plasma cells (Fig. 2d), with a ratio of about
60% of ­IgG4:IgG. The lesion was completely excised, and
she has received intralesional steroid therapy. Serum I­ gG4
levels were not elevated. Clinical consideration was given
to Rituximab therapy, but with clinical improvement after
surgery and steroids, no additional therapy has been under-
taken to this point.
Fig. 2  Eosinophilic angiocentric fibrosis. a A polypoid fragment
of tissue with a fibroinflammatory proliferation. b There is stromal
collagen deposition with a mixed inflammatory infiltrate, including Differential Diagnosis
eosinophils. c Onion-skin-type perivascular hyalinization is charac-
teristic. d There are > 50 I­gG4-positive plasma cells in a high power
field Reactive

The reactive category includes chronic rhinosinusitis,

necrosis, no leukocytoclastic reaction, no areas of nuclear inflammatory sinonasal tract polyps, granulomatosis with
dust, and no extravasated erythrocytes. There was no vas- polyangiitis, and eosinophilic angiocentric fibrosis, rec-
cular proliferation or phlebitis. The endothelial cells were ognizing that other reactive conditions may also be seen.
not raised or enlarged. Giant cells were not appreciated. Importantly, surface ulceration with reactive fibrosis and
There was a well-developed fibrosis, heavily deposited in mixed inflammation is a common finding due to friction
some areas, while sparse in others. In the heaviest areas, or digital manipulation (such as nose picking, pencils,

13
122 Head and Neck Pathology (2021) 15:120–129

cotton-tipped applicators, nasal hair scissors or tweezers, sinonasal polyps may develop, which often show a thick-
decorative piercing, foreign body, or the like). Traumatic ened basement membrane, and either a lymphoplasmacytic
lesions are more frequently unilateral than bilateral. Erosion or eosinophilic predominant infiltrate (Fig. 3b). A prominent
or ulceration overlying a neoplasm must also be excluded. submucosal hemorrhage with fibrin deposition or infarction
However, once it is recognized that the lesion is fibroinflam- may be seen in degenerative polyps [4]. Spindled cells are
matory, then further investigation can be undertaken. generally absent, but isolated stellate fibroblasts with hyper-
chromatic nuclei may be seen below the surface epithelium
Chronic Rhinosinusitis and Polyps or perivascular, considered a degenerative phenomenon.
They do not form sheets or show increased mitoses, a find-
Chronic rhinosinusitis is an inflammation of the nasal cavity ing more likely in embryonal rhabdomyosarcoma (also myo-
and/or paranasal sinuses. There are a myriad of etiologies genin or myo-D1 reactivity, not just desmin or smooth mus-
(allergies, infection, aspirin, toxins, medications) as well cle actin). Prominent fibrosis or fibrin may mimic amyloid,
as idiopathic [1–3]. Patients tend to be adults without sex but the acellular, extracellular, smudged eosinophilic qual-
predilection. Symptoms are usually nasal obstruction and ity of amyloid can be confirmed with a Congo red stain in
discharge, often bilateral. Viral and bacterial forms of acute selected cases. Sinonasal papilloma may have inflammation,
rhinosinusitis are not usually biopsied, and it is only when but show a proliferative transitional-type epithelium, endo-
chronic (> 12 weeks) that biopsy may be employed. The or exophytic growth, and intraepithelial microabscesses.
sinonasal mucosa is edematous and pale, and if concurrent
polyps are present, may yield a polypoid appearance. Antro- Granulomatosis with Polyangiitis
choanal polyps are usually seen in younger males, and are
typically unilateral. Granulomatosis with polyangiitis (GPA; formerly Wegener
Histologically, the surface may show metaplastic squa- granulomatosis) is a systemic immune complex vasculitis
mous epithelium, while the submucosa is edematous with affecting the sinonasal tract and kidneys most commonly
a mixed inflammatory infiltrate (Fig. 3a). The inflamma- [5]. Patients affected are usually middle aged with a slight
tory cells include lymphocytes, plasma cells, macrophages, male predominance. Symptoms are non-specific sinusitis
and eosinophils, the latter predominant in allergic dis- and often constitutional findings, with clinical examination
ease (Fig. 3b). Acute inflammation is more likely seen in demonstrating ulceration with crusting, sometimes progress-
a bacterial etiology. Fibrosis is limited, although may be ing to perforation and collapse of the nasal cartilages. By
more prominent with chronicity. Over time, inflammatory serology, autoantibodies to lysosomal components of neu-
trophils, specifically the cytoplasmic antigen (antineutrophil
cytoplasmic antibodies; c-ANCA) associated with antibodies
against proteinase 3 (PR3) is considered confirmatory in the
correct clinical and histologic setting [6].
The histologic triad of GPA is biocollagenolytic (necro-
biotic) necrosis, granulomatous inflammation, and vasculi-
tis, but all three features are seldom seen concurrently [7,
8]. “Biocollagenolytic” or “necrobiotic” necrosis refers to
zones of geographic basophilic necrosis with granular, cel-
lular debris usually of neutrophils (Fig. 3c). Isolated giant
cells may be seen, but well-formed granulomatous inflam-
mation is usually sparse to absent. Vasculitis affects small
to medium sized vessels and is the most specific finding,
but is difficult to detect in most cases (Fig. 3d). Fibrin in
the wall rather than full thickness involvement is more fre-
quent. Most biopsies show non-specific acute and chronic
inflammation with eosinophils and sometimes neutrophilic
microabscesses. Elastic stains may highlight affected ves-
Fig. 3  a An inflammatory sinonasal polyp with edematous stroma sels (Fig. 3d), while infectious disease studies are negative.
and inflammatory infiltrate. b There is a thickened basement mem- Churg-Strauss disease shows granulomatosis and vasculi-
brane and numerous eosinophils in this inflammatory polyp. c Granu- tis as an allergic reaction, and generally shows tissue and
lomatosis with polyangiitis (GPA) showing perivascular inflamma-
peripheral eosinophilia, with pulmonary disease commonly
tion with blue, granular biocollagenolytic debris. d An elastic stain
highlights destruction of a vessel wall, with inflammatory cells in the concurrently present. Crohn disease may occasionally mani-
background of this GPA case fest with sinonasal tract granulomatous findings, but this

13
Head and Neck Pathology (2021) 15:120–129 123

can be evaluated clinically. Cocaine abuse may show non- may have eosinophils, but shows high endothelial cells and
specific ulcers, but does not have vasculitis or fibrosis, while lymphoid cells without significant fibrosis. Granuloma
occasionally polarizable material from talc or other mate- faciale is almost always on the face, but mucosal disease is
rial used to “cut” cocaine can be identified [9]. Sarcoidosis exceedingly uncommon. While eosinophils are prominent,
shows tight, well-formed granulomas, seldom with coagula- nuclear dust is easily recognized, while concentric fibrosis
tive necrosis. is usually absent. Erdheim-Chester, a multiorgan, neoplastic
histiocytic disorder of CD68 positive, non-Langerhans his-
Eosinophilic Angiocentric Fibrosis ­(IgG4‑Related Disease) tiocytosis (CD1a and S100 protein negative) shows fibrosis
with histiocytes, but seldom affects the upper aerodigestive
Eosinophilic angiocentric fibrosis (EAF) is a rare, chronic tract and usually lacks eosinophils, while many show BRAF
obstructive upper aerodigestive tract lesion thought to be V600E.
part of ­IgG4-related diseases that demonstrates a submucosal
inflammatory, fibrosing, and tumefactive reaction [10–13]. Infectious
Patients are usually adults (5th decade), with females
affected more often than males, presenting with progres- Many infections can affect the sinonasal tract, with viral and
sive and prolonged airway obstruction (up to 20 years). The bacterial causes the most common. These, however, seldom
disease seems to progress and stabilize, but not ever resolve. give cause for clinical concern or biopsy. However, selected
The patients present with septal disease most often, but over infectious agents in the sinonasal tract do have unique fea-
time, involvement of the lateral wall and paranasal sinuses, tures which are highlighted here.
orbit, and subglottic area may be seen. There is often an
elevated serum ­IgG4 concentration (> 135 mg/dL), but Invasive Fungal Rhinosinusitis
systemic disease is usually absent. PR3-ANCA levels are
not elevated. About 25% of patients have concurrent granu- Acute invasive fungal rhinosinusitis (AIFRS) is an acute and
loma faciale [14]. Endoscopically, the lesions are tan-white fulminant, often life-threatening sinonasal tract infection that
to pink, fleshy to fibrotic submucosal masses, occasionally results in destruction of the sinonasal tract over a very short
with ulceration. time (days), often with skull base extension [16–18]. The
Histologically, EAF is characterized by concentric lay- majority of cases are caused by Aspergillus species (> 800
ered onion skin-type fibrosis around capillaries, venules, and species are recognized) [19] but many other fungi are impli-
small arteries, with a mixed inflammatory infiltrate domi- cated. Patients are usually adults, although younger immu-
nated by eosinophils (Fig. 2a and c). The disease usually nocompromised patients may also be affected, especially
shows an arc of development over time, with a temporal patients who are diabetic, being treated for hematolymphoid
evolution between vasculitis and fibrosis, with deposition malignancies, and post-transplantation. Patients present with
of more and more fibrosis around the chronically injured nasal discharge, facial/sinus pain, facial swelling, and with
vessels and a commensurate decrease in inflammation. How- disease progression, even blindness. Serum fungal antigen
ever, both phases can be seen in the same biopsy. The lami- testing may aid in diagnosis.
nated, scalloped fibrosis creates an onion-bulb appearance Histologically, there is true tissue necrosis and vessel
(Fig. 2c), quite unique in the sinonasal tract. The fibrosis is wall involvement (Fig. 4A), but often without a significant
occasionally storiform to whorled with spindled fibroblasts inflammatory response due to the rapid clinical onset. Fun-
giving a pseudogranulomatous appearance. The perivascular gal hyphae are seen within mucosal and submucosal tissues
fibrosis results in an obliterative phlebitis, one of the fea- as well as in and around vascular spaces (angioinvasive;
tures of ­IgG4-related diseases. Early in the disease there are Fig. 4a). Aspergillus hyphae are thin (2–5 µm) with acute
eosinophils within the capillaries and venules (Fig. 2b). A angle branching (45°) and septations that can aid in iden-
lymphoplasmacytic infiltrate may be seen. There is no necro- tification [16, 17, 20]. Special studies, including periodic
sis, biocollagenolytic necrosis, granulomatous inflammation, acid-Schiff stain (Fig. 4b) with fungal control or Gomori
or multinucleated giant cells [10, 13, 15]. Special stains for methenamine silver (GMS), in situ hybridization (using spe-
microorganisms are negative, but an elastic stain may high- cific fungal probes), and PCR can effectively identify fungi
light vessel wall destruction. Generally, > 50 ­IgG4-positive in invasive fungal sinusitis as well as in species identifica-
plasma cells in a high power field (40x magnification) helps tion in specimens with negative cultures [21]. A mycetoma
to confirm the diagnosis (Fig. 2D), along with an ­IgG4(+) is just a fungal ball without tissue invasion. Allergic fungal
plasma cells to IgG(+) plasma cells ratio (­IgG4:IgG) of sinusitis is an allergic reaction with degenerated eosinophils
> 40%. If the fibrosis is misconstrued to be a spindled resulting in alternating tide-lines of degenerated inflamma-
cell neoplasm, fibromatosis, solitary fibrous tumor, and tory cells with Charcot-Leyden crystals and fungal hyphae
schwannoma may be considered. Epithelioid hemangioma [22]. In general, none of the fungal infections have a true

13
124 Head and Neck Pathology (2021) 15:120–129

(Fig. 4c). Over time, the lesions become increasingly fibrotic

and less inflammatory, sometimes showing vasculitis, pseu-
doepitheliomatous hyperplasia, and ulceration. A spindled
component is generally absent [26, 27]. A Warthin-Starry
stain highlights the encapsulated, nonmotile, rod-shaped
Klebsiella bacilli within the Mikülicz cells (Fig. 4d), while
immunohistochemistry for the capsular antigen 3 is highly
specific and sensitive. Rosai-Dorfman shows emperipolesis
of plasma cells or lymphocytes, a finding not seen in rhino-
scleroma [28].

Mycobacterial Infections

Generally, mycobacterium infections include several spe-

cies within the genus, with tuberculosis (Mycobacterium
tuberculosis) and leprosy (Mycobacterium leprae) the most
Fig. 4  a Invasive fungal sinusitis showing fungal hyphae (black common considerations in the sinonasal tract, but also
arrow) within the vessel wall. b A PAS-Fungus control stain shows Mycobacterium avium-intracellulare for a mycobacterial
numerous fungal hyphae (black arrows) within the vessel wall and in spindle cell tumor [29, 30]. Infections caused by Mycobac-
the adjacent stroma. c Rhinoscleroma showing numerous plasma cells
terium leprae affect the cutaneous, mucosal, and periph-
and many foamy histiocytes (called Mikülicz cells). d A Warthin-
Starry stain highlights intracellular bacilli eral nerves, with the cooler peripheral sites (such as digits,
ears, and nose) commonly affected by the low infectivity
organism. However, in the context of this discussion, it is
fibroblastic reaction, but erosion or ulceration may result in the spindled cell tumor-like proliferation caused by myco-
reactive fibrosis. bacterium avium complex that is considered. Nearly all of
the patients are immunocompromised in some way, with
Rhinoscleroma human immunodeficiency virus (HIV) infected patients or
patients receiving immunosuppressive therapy most com-
Rhinoscleroma (sometimes called Hebra nose) is a rare, monly affected [29, 31]. There is no sex predilection, with
chronic infectious disease caused by Klebsiella rhinosclero- a wide age affected, although frequently in young adults. A
matis, a Gram-negative coccobacillus from the Enterobac- mass lesion is detected clinically, whether as lymph node
teriaceae family, that affects the nasal cavity and nasophar- enlargement, a subcutaneous nodule, or mucosal mass [29].
ynx [17, 23–25]. Young adults are most frequently affected, The nasal septum is most commonly affected [29, 30, 32].
females more often than males, primarily in endemic The lesions are unencapsulated, partially to com-
regions, such as parts of South America, Central America, pletely effacing the normal architecture by a proliferation
Africa, India, and Indonesia. There are three overlapping of fibroblast-like spindle cells. The cellular proliferation
clinical phases: (a) rhinitic (ozena, catarrhal, exudative) is composed of bland-appearing, spindle-shaped cells in
stage characterized by a foul-smelling mucopurulent nasal a haphazard to storiform pattern. The spindled cells have
discharge with nasal obstruction and erythema; (b) granu- eosinophilic, granular appearing cytoplasm, as these fac-
lomatous (florid, proliferative) stage marked by mucosal ultative histiocytes phagocytose the infectious mycobacte-
thickening by numerous small masses and subsequent nasal rial organisms (Fig. 5a). Isolated areas of necrosis may be
obstruction; (c) scleroma (fibrotic, cicatrical) stage, char- seen, but in general a well-formed granuloma is not seen.
acterized by marked scarring, tissue retraction, and nasal Further, multinucleated giant cells and foamy histiocytes
stenosis. MacConkey agar is used to grow the fastidious are generally focal or absent. A background of inflamma-
organism, but is only positive in about 50% of cases. tory cells, including lymphocytes and plasma cells are seen
Grossly there are friable nasal polyps, which become [30, 32]. A Ziehl-Neelsen stain will highlight innumer-
more densely fibrotic with time. Rhinoscleroma is usually able intracytoplasmic bacilli (Fig. 5b), while fluorescence
biopsied during the florid or fibrotic stage, where there is an microscopy also identifies the organisms. Nuclei acid probes
expanded submucosa by an inflammatory infiltrate includ- can be used to confirm the exact species [33]. Importantly,
ing lymphocytes, plasma cells, neutrophils, and histiocytes. the histiocyte/macrophages are immunoreactive with CD68,
Russell bodies (cytoplasmic inclusions of immunoglobulin) lysozyme, S100 protein, and muscle specific actin [29, 31,
are frequent. The diagnostic histologic finding is “Mikülicz 32], but CD31, CD34, ERG, FLI1, and HHV-8 are nega-
cells,” large vacuolated histiocytes filled with organisms tive. Kaposi sarcoma may be concurrently present given the

13
Head and Neck Pathology (2021) 15:120–129 125

contraceptives) (male: female, 1:4), and then an equal dis-

tribution beyond 40 years of age [35–37]. Patients present
with unilateral epistaxis and/or an obstructive painless mass
present for a short duration due to the urgent nature of the
symptoms. The anterior septum (specifically the Little area)
and the turbinate (usually anterior tip) are more commonly
affected in the sinonasal tract than are the paranasal sinuses
[38, 39].
Tumors often present as a polypoid (pedunculated) nod-
ule, soft and compressible. A collarette of epithelium is often
noted at the stalk or base, with secondary changes (ulcera-
tion, hemorrhage, thrombosis) frequent. There is a lobular,
circumscribed anastomosing network of capillaries with
plump endothelial cells and often a proliferation of pericytes
in a fibromyxoid stroma arranged in one or more lobules
(Fig. 5c). Each lobule is composed of a large central vein
Fig. 5  a A mycobacterial spindle cell tumor shows a spindled cell (“feeder” vessel) surrounded by aggregates of small variably
population with numerous inflammatory cells. b An AFB stain sized capillaries with plump endothelial cells (Fig. 5d), with
reveals innumerable intracellular organisms within the histiocytes. an overlying epithelium (often ulcerated or atrophic). The
c A lobular capillary hemangioma showing a subepithelial prolifera-
vessel lumina may be indistinct to slightly open, with the
tion of vessels arranged in a lobular pattern. d There is a central vein
surrounded by a cellular endothelial-lined proliferation of slit-like packed vessels surrounded by intact pericytes. Mitoses are
vessels invariably present but without atypical forms. If the mass is
superficial in location, secondary, nonspecific changes may
be present, such as a granulation-type tissue with numer-
strong HIV-association, with a positive HHV-8 immuno- ous capillaries and venules disposed radially to the surface
histochemistry. Leiomyoma usually have more “box-like” with a markedly edematous stroma containing mixed inflam-
nuclei, perinuclear vacuoles, and lack inflammation. matory cells (neutrophils, lymphocytes, plasma cells, mast
cells) and extravasated erythrocytes. There is often an arc
Neoplastic of development, with early lesions having a greater number
of vessels and edema to a more fibrotic lesion with fewer
Neoplasms of the upper aerodigestive tract frequently show vessels. However, granulation tissue does not have a lobular
a spindled morphology, with spindle cell squamous cell architecture. Bacillary angiomatosis is also a disorder seen
carcinoma and spindle cell melanoma the most frequent, more frequently in HIV-infected or immunocompromised
while glomangiopericytoma, leiomyoma, peripheral nerve patients, showing clusters of neutrophils and lymphocytes
sheath tumors, solitary fibrous tumor, biphenotypic sinona- associated with the vascular proliferation, showing pleomor-
sal sarcoma, leiomyosarcoma, and rhabdomyosarcoma are phic bacilli with a Warthin-Starry stain [40]. Angiosarcoma
additional mesenchymal neoplasms to consider in this site. can be quite deceptively low grade, but generally displays
However, most of these lesions do not have a prominent a freely anastomosing network of atypical endothelial-lined
inflammatory component associated with the neoplastic spaces, frequently with atypical mitoses, destructive growth,
proliferation and so these tumors are not further discussed. and tumor necrosis [41].
However, several lesions may have an admixed fibroinflam-
matory population. Inflammatory Myofibroblastic Tumor

Lobular Capillary Hemangioma Inflammatory myofibroblastic tumor (IMT) is a neoplasm

composed of myofibroblastic spindle cells accompanied by
Lobular capillary hemangioma is a benign capillary pro- an inflammatory infiltrate of plasma cells, lymphocytes, and/
liferation with a microscopically distinctive lobular archi- or eosinophils [42]. Up to 60% of tumors have an anaplastic
tecture frequently with a friable surface, associated with a lymphoma kinase (ALK) gene (2p23) rearrangement with a
rich inflammatory infiltrate with a predilection to the oral wide variety of fusion partners. There is a higher frequency
cavity and sinonasal tract [34]. There is a difference in sexes of ALK rearrangements in children and young adults than in
based on age, with an initial peak in children (first decade) patients > 40 years of age at presentation [43], and within
and adolescent males (male: female, 4:1), females in the the head and neck, patients tend to be older than patients
reproductive years (especially when pregnant or taking oral with tumors of other sites [42, 44–46]. For head and neck

13
126 Head and Neck Pathology (2021) 15:120–129

IMT, there is no sex predilection. Symptoms are nonspecific. keratin reactivity seen in up to 30% of cases [48]. IgG and
Within the sinonasal tract, the maxillary sinus is most com- ­IgG4-positive plasma cells may be seen, the latter raising
monly affected [46]. consideration for I­ gG4-related disease [50–52]. Desmoid-
Tumors are identified below the surface epithelium, type fibromatosis has more of a purposeful direction to
which may be ulcerated. Bone invasion may be seen, while the collagen, little to no inflammation, and shows a strong
lymphovascular or perineural invasion is uncommon. There nuclear ß-catenin reaction with a negative ALK.
is no circumscription or encapsulation. The spindled myofi-
broblastic cells are loosely arranged, showing a vague stori- Extranodal NK/T‑Cell Lymphoma, Nasal Type
form or cartwheel architecture (Fig. 6a). The cells are spin-
dled, stellate, slightly plump epithelioid to gangliocytic in Extranodal NK/T-cell lymphoma, nasal type (ENKL) is
appearance, set within a myxoid, loose background stroma extranodal when it develops in the sinonasal tract and is
rich with inflammatory cells (lymphocytes, plasma cells, a lymphoma of mature NK-cell or T-cell lineage showing
neutrophils, eosinophils). Axonal or spider-like ganglion angiocentric destruction with prominent tumor cell necrosis,
cells with eccentric nuclei can usually be detected (Fig. 6b). a cytotoxic phenotype, and a near constant association with
There is vesicular, open nuclear chromatin, small nucleoli, Epstein-Barr virus (EBV), irrespective of ethnicity [53].
and frequent intranuclear cytoplasmic inclusions. There is In endemic regions (such as East Asia, Central and Latin
often a fibrillar quality to the cytoplasm. Occasional tumors America), ENKL accounts for about 15% of all lymphomas
are more cellular with compact fascicles of spindled cells [53, 54]. ENKL develops over a wide age range (1–83 years)
and a more collagenized stroma. Histiocytes, including but tends to be seen most often in younger adults (mean
multinucleated forms, may be seen. Three main histological age at presentation: 35–45 years), with males affected more
patterns are recognized: myxoid, hypercellular, and hypocel- commonly than females by a 2.4:1 ratio [53–55]. Initial
lular patterns, suggested to be a chronologic progression symptoms are non-specific, with swelling, nasal obstruction,
[47, 48]. About 60% of head and neck IMTs, especially in difficulty breathing, and erythema, but with disease progres-
patients < 40 years of age, show ALK immunoreactivity, a sion, extensive mid-facial destruction develops with asso-
finding that correlates with ALK gene rearrangements, and ciated epistaxis, pain, and paresthesia. Importantly, more
the pattern of reactivity matching gene fusions [43, 49]. The than one biopsy is often required, which results in delay in
spindled cells also show a focal to patchy, weak to strong diagnosis [56]. Ulceration, necrosis, nasal septal destruction,
reactivity for SMA, MSA, calponin, and desmin, with focal and palatal perforation or destruction are common.
Epithelial ulceration is common, occasionally associated
with pseudoepitheliomatous hyperplasia during healing [57].
Epitheliotropism is also noted, with micro-abscesses of neo-
plastic cells seen in the epithelium. Angiocentric and angi-
odestructive growth are nearly always present (Fig. 6c), with
atypical cells seen within the vessel walls associated with
fibrinoid degeneration of the walls and/or fibrin thrombi
within the vessels. Extensive, geographic, coagulative,
ischemic-type necrosis results. Minor mucoserous glands
are destroyed by the infiltrate, and thus appear reduced in
number. There is a very broad cytomorphologic appearance,
usually related to an arc of development. A reactive inflam-
matory background includes lymphocytes, plasma cells, his-
tiocytes, and eosinophils with medium- to large cells that
show nuclear pleomorphism, irregular, folded, and elongated
nuclei, coarse granular chromatin, and moderate cytoplasm
(Fig. 6d)[58]. Mitoses are easily identified and include atypi-
cal forms. Multinucleated giant cells and granulomas are
usually absent. Elastic stains may aid in identifying angi-
Fig. 6  a An inflammatory myofibroblastic tumor (IMT) shows a hap-
hazard spindled cell proliferation associated with a mixed inflam- odestruction. The neoplastic cells are usually positive with
matory infiltrate. b A hypocellular IMT with several ganglion-like CD2, CD56, and cytoplasmic CD3-epsilon and negative
myofibroblasts (black arrow). c A low power of an extranodal NK/T- with CD5. EBV is universally expressed, detected with
cell lymphoma, nasal type (ENKL) with areas of necrosis and angi-
in situ hybridization for EBV-encoded small RNA (EBER;
odestruction (white arrow). d High power of an ENKL showing
remarkably atypical and convoluted cells, highlighted by a strong Fig. 6d, inset) [59, 60]. There is variable reactivity with
nuclear EBER (dark blue nuclei; inset) CD43, CD45RO (UCHL1), CK7, and p53 while negative

13
Head and Neck Pathology (2021) 15:120–129 127

with CD4, CD8, CD16, and CD57 [61, 62]. In about 30% of 6. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-asso-
cases, a T-cell lineage is present, demonstrating cytotoxic ciated vasculitides. Am J Med. 2004;117(1):39–50.
7. Devaney KO, Travis WD, Hoffman G, et al. Interpretation of
T-cell granules, identified by positive immunoreactions with head and neck biopsies in Wegener’s granulomatosis. A patho-
granzyme B, TIA1, and/or perforin, along with CD5, CD8, logic study of 126 biopsies in 70 patients. Am J Surg Pathol.
and T-cell receptors (gamma delta or alpha beta) [63–65]. 1990;14(6):555–64.
While a large number of lesions are in the differential, nearly 8. Heffner DK. Wegener’s granulomatosis is not a granulomatous
disease. Ann Diagn Pathol. 2002;6(5):329–33.
all are negative with EBER, which can be a very useful 9. Seyer BA, Grist W, Muller S. Aggressive destructive midfacial
guide in diagnosis. lesion from cocaine abuse. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 2002;94(4):465–70.
10. Ahn J, Flanagan M. Eosinophilic angiocentric fibrosis: a review
and update of its association with immunoglobulin G4-related
Conclusions disease. Arch Pathol Lab Med. 2018;142(12):1560–3.
11. Helliwell TR. Non-infectious inflammatory lesions of the sinona-
Even though there is wide diversity in the fibroinflammatory sal tract. Head Neck Pathol. 2016;10(1):32–9.
12. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone
category of sinonasal tract lesions, a systematic approach JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related
based on general categories (reactive, infectious, neoplas- systemic disease. Am J Surg Pathol. 2011;35(5):701–6.
tic) and proceeding from the most common to the rare, will 13. Thompson LD, Heffner DK. Sinonasal tract eosinophilic angi-
allow for appropriate diagnosis utilizing selected ancillary ocentric fibrosis. A report of three cases. Am J Clin Pathol.
2001;115(2):243–8.
techniques. 14. Stelini RF, Moysés MD, Cintra ML, et al. Granuloma faciale
and eosinophilic angiocentric fibrosis: similar entities in dif-
Acknowledgements Presented at the North American Society of Head ferent anatomic sites. Appl Immunohistochem Mol Morphol.
and Neck Pathology Companion Society Meeting at the 110th Annual 2017;25(3):213–20.
Meeting of the United States and Canadian Academy of Pathology, 15. Jain R, Robblee JV, O’Sullivan-Mejia E, et al. Sinonasal eosino-
Baltimore, MD: March 17, 2021. philic angiocentric fibrosis: a report of four cases and review of
literature. Head Neck Pathol. 2008;2(4):309–15.
Compliance with Ethical Standards 16. Das A, Bal A, Chakrabarti A, Panda N, Joshi K. Spectrum of fun-
gal rhinosinusitis; histopathologist’s perspective. Histopathology.
2009;54(7):854–9.
Funding No external funding was obtained for this study. 17. Montone KT. The molecular genetics of inflammatory, autoim-
mune, and infectious diseases of the sinonasal tract: a review.
Conflict of interest The author declares he has no conflict of interest as Arch Pathol Lab Med. 2014;138(6):745–53.
it relates to this review. 18. Smith A, Thimmappa V, Shepherd B, et al. Invasive fungal sinusi-
tis in the pediatric population: systematic review with quantita-
Ethical Approval This review article was performed in accordance with tive synthesis of the literature. Int J Pediatr Otorhinolaryngol.
ethical standards and did not require informed consent. The opinions 2016;90:231–5.
or assertions contained herein are the private views of the author and 19. Hawksworth DL. Naming Aspergillus species: progress towards
are not to be construed as official or as reflecting the views of Southern one name for each species. Med Mycol. 2011;49(Suppl 1):70–6.
California Permanente Medical Group. 20. Papagiannopoulos P, Lin DM, Al-Khudari S, et al. Utility of
intraoperative frozen sections in surgical decision making for
acute invasive fungal rhinosinusitis. Int Forum Allergy Rhinol.
2017;7(5):502–7.
21. Cho HJ, Hong SD, Kim HY, Chung SK, Dhong HJ. Clini-
References cal implications of serum galactomannan measurement in
patients with acute invasive fungal rhinosinusitis. Rhinology.
1. Fokkens W, Lund V, Bachert C, et al. EAACI position paper 2016;54(4):336–41.
on rhinosinusitis and nasal polyps executive summary. Allergy. 22. Lara JF, Gomez JD. Allergic mucin with and without fungus: a
2005;60(5):583–601. comparative clinicopathologic analysis. Arch Pathol Lab Med.
2. Hellquist HB. Nasal polyps update. Histopathology. Allergy 2001;125(11):1442–7.
Asthma Proc. 1996;17(5):237–42. 23. Fawaz S, Tiba M, Salman M, Othman H. Clinical, radiological
3. Passàli D, Bellussi L, Hassan HA, et al. Consensus conference and pathological study of 88 cases of typical and complicated
on nasal polyposis. Acta Otorhinolaryngol Ital. 2004;24(2 Suppl scleroma. Clin Respir J. 2011;5(2):112–21.
77):3–61. 24. Gaafar HA, Gaafar AH, Nour YA. Rhinoscleroma: an updated
4. Sheahan P, Crotty PL, Hamilton S, Colreavy M, McShane D. experience through the last 10 years. Acta Otolaryngol.
Infarcted angiomatous nasal polyps. Eur Arch Otorhinolaryngol. 2011;131(4):440–6.
2005;262(3):225–30. 25. Zhong Q, Guo W, Chen X, et al. Rhinoscleroma: a retrospective
5. Lutalo PM, D’Cruz DP. Diagnosis and classification of granu- study of pathologic and clinical features. J Otolaryngol Head Neck
lomatosis with polyangiitis (aka Wegener’s granulomatosis). J Surg. 2011;40(2):167–74.
Autoimmun. 2014;48–49:94–8. 26. Heffner DK. Plasma cell granuloma in the nasal cavity. Cancer.
1991;68(11):2490.

13
128 Head and Neck Pathology (2021) 15:120–129

27. Thompson LDR. Rhinoscleroma. Ear Nose Throat J. 2002;81:8. 48. Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary
28. Chou TC, Tsai KB, Lee CH. Emperipolesis is not pathogno- inflammatory myofibroblastic tumor (inflammatory pseudotu-
monic for Rosai-Dorfman disease: rhinoscleroma mimicking mor). A clinicopathologic and immunohistochemical study of
Rosai-Dorfman disease, a clinical series. J Am Acad Dermatol. 84 cases. Am J Surg Pathol. 1995;19(8):859–72.
2013;69(6):1066–7. 49. Wang Z, Zhao X, Li K, et al. Analysis of clinical features and
29. Sfeir MM, Schuetz A, Van Besien K, et al. Mycobacterial spin- outcomes for inflammatory myofibroblastic tumors in China:
dle cell pseudotumour: epidemiology and clinical outcomes. J 11 years of experience at a single center. Pediatr Surg Int.
Clin Pathol. 2018;71(7):626–30. 2016;32(3):239–43.
30. Ilyas S, Youssef D, Chaudhary H, Al-Abbadi MA. Myoc- 50. Chougule A, Bal A. IgG4-related inflammatory pseudotumor:
bacterium-avium intracellulare associated inf lammatory a systematic review of histopathological features of reported
pseudotumor of the anterior nasal cavity. Head Neck Pathol. cases. Mod Rheumatol. 2017;27(2):320–5.
2011;5(3):296–301. 51. Ryu G, Cho HJ, Lee KE, et al. Clinical significance of IgG4 in
31. Brandwein M, Choi HS, Strauchen J, Stoler M, Jagirdar J. Spin- sinonasal and skull base inflammatory pseudotumor. Eur Arch
dle cell reaction to nontuberculous mycobacteriosis in AIDS Otorhinolaryngol. 2019;276(9):2465–73.
mimicking a spindle cell neoplasm. Evidence for dual histio- 52. Taylor MS, Chougule A, MacLeay AR, et al. Morphologic
cytic and fibroblast-like characteristics of spindle cells. Vir- overlap between inflammatory myofibroblastic tumor and IgG4-
chows Arch A. 1990;416(4):281–6. related disease: lessons from next-generation sequencing. Am J
32. Gunia S, Behrens MH, Stosiek P. Mycobacterial spindle cell Surg Pathol. 2019;43(3):314–24.
pseudotumor (MSP) of the nasal septum clinically mimicking 53. Sanchez-Romero C, Paes de Almeida O, Rendon Henao J,
Kaposi’s sarcoma: case report. Rhinology. 2005;43(1):70–1. Carlos R. Extranodal NK/T-cell lymphoma, nasal type in
33. Herdman AV, Steele JC Jr. The new mycobacterial species- guatemala: an 86-case series emphasizing clinical presen-
emerging or newly distinguished pathogens. Clin Lab Med. tation and microscopic characteristics. Head Neck Pathol.
2004;24(3):651–90 vi. 2019;13(4):624–34.
34. Thompson LDR, Fanburg-Smith JC. Update on select benign 54. Cao C, Feng J, Gu H, et al. Distribution of lymphoid neo-
mesenchymal and meningothelial sinonasal tract lesions. Head plasms in Northwest China: analysis of 3244 cases according
Neck Pathol. 2016;10(1):95–108. to WHO classification in a single institution. Ann Diagn Pathol.
35. Takaishi S, Asaka D, Nakayama T, et al. Features of sinonasal 2018;34:60–5.
hemangioma: a retrospective study of 31 cases. Auris Nasus 55. Feng Y, Rao H, Lei Y, et al. CD30 expression in extranodal
Larynx. 2017;44(6):719–23. natural killer/T-cell lymphoma, nasal type among 622 cases of
36. Kim JS, Kwon SH. Sinonasal hemangioma: diagnosis, treat- mature T-cell and natural killer-cell lymphoma at a single insti-
ment, and follow-up of 37 patients at a single center. J Oral tution in South China. Chin J Cancer. 2017;36(1):43.
Maxillofac Surg. 2017;75(8):1775–83. 56. Haverkos BM, Pan Z, Gru AA, et al. Extranodal NK/T cell lym-
37. Bett JVS, Batistella EA, Melo G, et al. Prevalence of oral phoma, nasal type (ENKTL-NT): an update on epidemiology,
mucosal disorders during pregnancy: a systematic review and clinical presentation, and natural history in North American and
meta-analysis. J Oral Pathol Med. 2019;48(4):270–7. European cases. Curr Hematol Malig Rep. 2016;11(6):514–27.
38. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cav- 57. Ling YH, Zhu CM, Wen SH, et al. Pseudoepitheliomatous
ity, paranasal sinuses, and nasopharynx: a clinicopatho- hyperplasia mimicking invasive squamous cell carcinoma in
logic study. I. General features and vascular tumors. Cancer. extranodal natural killer/T-cell lymphoma: a report of 34 cases.
1974;33(5):1275–88. Histopathology. 2015;67(3):404–9.
39. Kapadia SB, Heffner DK. Pitfalls in the histopathologic diag- 58. Hasserjian RP, Harris NL. NK-cell lymphomas and leukemias:
nosis of pyogenic granuloma. Eur Arch Otorhinolaryngol. a spectrum of tumors with variable manifestations and immu-
1992;249(4):195–200. nophenotype. Am J Clin Pathol. 2007;127(6):860–8.
40. Fatahzadeh M, Schwartz RA. Oral Kaposi’s sarcoma: a review 59. Swerdlow SH, Jaffe ES, Brousset P, et al. Cytotoxic T-cell and
and update. Int J Dermatol. 2013;52(6):666–72. NK-cell lymphomas: current questions and controversies. Am
41. Nelson BL, Thompson LD. Sinonasal tract angiosarcoma: a J Surg Pathol. 2014;38(10):e60-71.
clinicopathologic and immunophenotypic study of 10 cases with 60. Kuo TT, Shih LY, Tsang NM. Nasal NK/T cell lymphoma in
a review of the literature. Head Neck Pathol. 2007;1(1):1–12. Taiwan: a clinicopathologic study of 22 cases, with analysis of
42. Zhu Z, Zha Y, Wang W, et al. Inflammatory myofibroblastic histologic subtypes, Epstein-Barr virus LMP-1 gene association,
tumors in paranasal sinus and nasopharynx: a clinical retrospec- and treatment modalities. Int J Surg Pathol. 2004;12(4):375–87.
tive study of 13 cases. Biomed Res Int. 2018;2018:7928241. 61. Quintanilla-Martinez L, Franklin JL, Guerrero I, et al. Histo-
43. Yamamoto H, Yoshida A, Taguchi K, et al. ALK, ROS1 and logical and immunophenotypic profile of nasal NK/T cell lym-
NTRK3 gene rearrangements in inflammatory myofibroblastic phomas from Peru: high prevalence of p53 overexpression. Hum
tumours. Histopathology. 2016;69(1):72–83. Pathol. 1999;30(7):849–55.
44. Dalton BG, Thomas PG, Sharp NE, et al. Inflammatory myofi- 62. Jaffe ES, Chan JK, Su IJ, et al. Report of the workshop on nasal
broblastic tumors in children. J Pediatr Surg. 2016;51(4):541–4. and related extranodal angiocentric T/natural killer cell lympho-
45. Desai SV, Spinazzi EF, Fang CH, et al. Sinonasal and ventral mas. definitions, differential diagnosis, and epidemiology. Am
skull base inflammatory pseudotumor: a systematic review. J Surg Pathol. 1996;20(1):103–11.
Laryngoscope. 2015;125(4):813–21. 63. Jhuang JY, Chang ST, Weng SF, et al. Extranodal natural
46. He CY, Dong GH, Yang DM, Liu HG. Inflammatory myofibro- killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher
blastic tumors of the nasal cavity and paranasal sinus: a clin- frequency of T-cell lineage and poor survival for extranasal
icopathologic study of 25 cases and review of the literature. Eur tumors. Hum Pathol. 2015;46(2):313–21.
Arch Otorhinolaryngol. 2015;272(4):789–97. 64. Pongpruttipan T, Sukpanichnant S, Assanasen T, et al. Extran-
47. Coffin CM, Dehner LP. Fibroblastic-myofibroblastic tumors odal NK/T-cell lymphoma, nasal type, includes cases of natural
in children and adolescents: a clinicopathologic study of 108 killer cell and αβ, γδ, and αβ/γδ T-cell origin: a comprehensive
examples in 103 patients. Pediatr Pathol. 1991;11(4):569–88.

13
Head and Neck Pathology (2021) 15:120–129 129

clinicopathologic and phenotypic study. Am J Surg Pathol. T-lymphocyte/natural killer cell lymphomas from Mexico. Mod
2012;36(4):481–99. Pathol. 1998;11(8):754–61.
65. Elenitoba-Johnson KS, Zarate-Osorno A, Meneses A, et al.
Cytotoxic granular protein expression, Epstein-Barr virus strain Publisher’s Note Springer Nature remains neutral with regard to
type, and latent membrane protein-1 oncogene deletions in nasal jurisdictional claims in published maps and institutional affiliations.

13