Head and Neck Pathol

DOI 10.1007/s12105-017-0787-0

ORIGINAL PAPER

Update From The 4th Edition of the World Health Organization

Classification of Head and Neck Tumours: Nasopharynx
1 2
Edward B. Stelow · Bruce M. Wenig
incidence rate of more than
15 per 100,000 person years
whereas in the United States
the incidence rate is less
than 1 per 100,000 person
years. This is believed to be
caused by differences in
popu-lation susceptibilities
Received: 27 November 2016 / Accepted: 2 February 2017 © Springer and exposures.
Science+Business Media New York 2017
The most obvious
Abstract The current WHO classification system for tumors differences regarding the
of the head and neck has made few changes from the Nasopharyngeal disease reflect the tumors’
previous edition with regards to tumors of the naso-pharynx. Carcinoma relationship to Epstein–Barr
The classification system is discussed here with particular virus (EBV). In parts of the
attention to nasopharyngeal carcinoma, naso-pharyngeal In spite of the relatively non- world with so-called
papillary adenocarcinoma, salivary gland anlage tumor, hairy specific nature of the appel- “endemic” nasopharyngeal
polyp, juvenile angiofibroma, and other tumors. lation, “nasopharyngeal carcinoma, the vast majority
carcinoma” remains the (>95%) of cases are
Keywords Nasopharynx · Carcinoma · Squamous cell diagnostic term of choice for associated with EBV as can
carcinoma · Papillary · Adenocarcinoma · Angiofibroma · all squamous cell carcinomas be shown by a vari-ety of
Salivary gland · Anlage · Angiofibroma · WHO (SCCs) of the nasopharynx. methodologies, most often
The WHO then subtypes in situ hybridization for
these cancers as non- EBV-encoded small RNAs
Introduction keratinizing and keratinizing (EBERs) [2]. It is believed
types, as well as basaloid
that people from these areas
Owing to the restricted anatomic area of the nasopharynx and SCC. Non-keratinizing are more genetically
correlating limited number of disease/tumor entities, the 4th tumors are further sub- susceptible to the disease
edition of the World Health Organization (WHO) categorized as
undifferentiated or with a number of human
Classification of Head and Neck Tumors has few changes leukocyte antigens (HLA)
(e.g., addition of new entities, substantial change in ter- differentiated (Fig. 1). This
haplotypes being linked to
minology, etc.) from the previous (3rd) edition. Indeed, only classifica-tion system is in the disease (e.g., HLA-A2,
minor semantic changes, mentioned below, have been made. keeping with the previous AW19, BW46 and B17) [3,
(3rd) edition.
4]. Other genetic sus-
There are fewer than ceptibilities, such as
100,000 cases of mutations of the cytochrome
Special Issue: World Health Organization Classification Update *\ nasopharyngeal carcinoma P450s involved with
Edward B. Stelow
in the world every year [1]. metabolism of nitrosamines
The majority of these have been pos-tulated [5].
\ edstelow@yahoo.com tumors arise in areas of Such theories are potentially
southeastern Asia. Indeed, credible as salted fish and
1
\ Anatomic Pathology, University of Virginia Health System, geographical incidence other preserved foods are
Box 800214, Jefferson Park Ave., Charlottesville, VA 22908, USA varies considerably as some considered environmen-tal
2
\ H. Lee Moffitt Cancer Center and Research Institute, Tampa, south-eastern Asian risk factors for the disease
FL, USA populations have an [6]. It should be noted that

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Fig. 1  Nonkeratinizing nasopharyngeal carcinoma: These tumors are further sub-classified as differentiated (a) and undifferentiated (b) based
upon whether epithelial differentiation is more or less apparent
designation HPV-associated have suggested that the
carcinoma for such prognosis for HR-HPV-
while EBV appears necessary for the development of most oropharyn-geal cancers. related tumors may be
non-keratinizing SCCs of the nasopharynx, viral infection in between that of EBV-related
itself is insufficient to cause the malignancy. Finally, it should be noted SCCs and those tumors not
that some SCCs centered in related to oncogenic viruses
the nasopharynx are [11].
EBV plays much less of a role in the development of
keratinizing SCC, especially in areas where the malignancy is secondary to HR-HPV
not considered to be endemic [2]. Keratinizing SCC appears to infection [11].
be related to smoking, akin to the keratinizing SCC at other sites
within the upper aerodigestive tract [7]. Keratinizing SCC is Other Tumors
more likely than non-keratinizing SCC to be locally advanced at This should not be
its presentation and less likely to be metastatic to locoregional surprising as the majority of
lymph nodes [8]. Among malignant salivary
oropharyn-geal SCCs are gland tumors, adenoid cystic
secondary to HR-HPV carcinoma is the most
As keratinizing and non-keratinizing nasopharyngeal infection as well as common type to occur in the
carcinomas develop in vastly different proportions in dif- approximately a quarter of naso-pharynx, is
ferent parts of the world, present in patients with different sinonasal carcinomas. As at histologically identical to its
ages and risk factors for the disease, and at different clinical those sites, in the more common salivary gland
stages, it is not hard to imagine that showing EBV or even nasopharynx such SCCs are counterpart, shows the
keratinization as an independent prognostic factor has been typically non-keratinizing presence of MYB-NFIB gene
difficult, although many have done so [8, 9]. Still, as stud-ies and can appear similar to fusion, and shares overall
have been mixed, there is not a consensus regarding the tumors associ-ated with similar biologic behavior.
prognostic significance of the histologic subtype of naso- EBV infection. Two other epithelial tumors
pharyngeal carcinoma or of the tumors’ EBV status. The Differentiation is predicated appear unique or relatively
most powerful prognostic factor of nasopharyngeal carci- unique to the nasopharynx,
on testing and identifying of
noma is stage at presentation [10]. nasopharyngeal pap-illary
HPV (e.g., p16
adenocarcinoma and salivary
immunohisto-chemical gland anlage tumor. A few
It is perhaps due only the entrenchment of name “naso- staining, in situ other neoplasms or
pharyngeal carcinoma” that the WHO did not suggest clas- hybridization and/or pseudoneoplasms occur
sification of the disease either by keratinization or EBV sta- polymerase chain reaction) solely or relatively commonly
tus (e.g., EBV-associated nasopharyngeal carcinoma). This is or EBV (e.g., EBER). in the nasopharynx and are
in contrast to high-risk human papillomavirus (HR-HPV) Although the prog-nostic mentioned in this section of
status in the oropharynx. At that site, however, HR-HPV meaning of EBV viral the classification system.
status has been universally accepted to be a significant infection at this site is These include hairy polyps,
prognostic factor engendering consideration of using the debated (see above), some ectopic pituitary adenomas,
and craniophar-yngioma (discussed within the category of and cartilage tumors” and
“other lesions”), as well as chordoma and juvenile angiofibroma “soft tissue tumors,”
(the sole lesions discussed within the sections devoted to “bone respectively).
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Head and Neck Pathol\

tubules lined by a single layer of presumed ectopic pituitary

bland columnar to cuboidal epi- tissue (ectopic pituitary
As the name implies, nasopharyngeal papillary adeno- thelial cells
carcinomas occur in the nasopharynx and are papillary. They adenomas) [17]. The tumors
are, invariably, low grade. The tumors are very rare and typically present as mass
boys affected approximately lesions, however endocrine
represent less than 1% of nasopharyngeal malignan-cies.
3 times more commonly disturbances such as
They occur over a wide age range (reported ages: 9–64
than girls. Tumors contain Cushing’s syndrome or
years), equally in both sexes, and can involve any part of the
an admixture of epithelial acromegaly also may be
nasopharynx. Most patients present with obstruction,
and stro-mal elements (Fig. present. The tumors
although rhinorrhea, bleeding and otitis media or hearing-
3). Epithelial elements typically have features of
related issues occur. Most patients have been treated with
consist of both papillary and lower grade neuroen-
surgery alone, although some have also received radia-tion
tubular gland proliferations docrine epithelial neoplasms
therapy. No patients have developed recurrences or
with solid and cystic with nests, rosettes, ribbons
metastases.
squamous nests. Stromal and pseudoglandular
tissue consists of bland structures composed of
Nasopharyngeal papillary adenocarcinomas are com-posed of spindled cells arranged at
complex arborizing papillae with hyalinized fibro-vascular cores monomor-phic epithelioid
variable cellularity. These or plasmacytoid cells.
and glands (Fig. 2). The lesions are invasive and typically
lesions are benign and do Mitotic figures are usually
involve the surface epithelium, focally merg-ing with non-
neoplastic epithelium. Papillae are lined by a single layer of not recur after resection. infrequent and the
cuboidal to columnar cells that have a mod-erate amount of This tumor is now discussed chromatin pattern is
eosinophilic cytoplasm. Nuclei vary from round to oval and within the section dedicated typically granular. Nuclear
have moderate membrane irregularity with vesicular to clear to salivary gland tumors atypia and nucleoli may
chromatin, similar to the nuclei seen with papillary thyroid rather than in the “benign sometimes be seen and
carcinomas. Psammomatoid calcifi-cations are seen in one-third epithelial tumors” section. tumors may even resemble
of cases. Mitotic figures are uncommon and necrosis is rarely poorly differenti-ated
seen. Perineural and angi-olymphatic invasion are not seen. Hairy polyps are likely carcinomas.
developmental Immunohistochemistry can
Tumours express EMA, CK5/6 and often CK7 [12, 13]. A abnormalities of the 1st or be helpful and most tumors
subset of cases express CK19 and TTF1 and has been 2nd branchial cleft. They (but not all) will react with
referred to as “thyroid-like low-grade nasopharyngeal pap- are thus considered by some antibodies to cytokeratins
illary adenocarcinoma.” These cases do not express thy- to be accessory auricles and endocrine antigens such
roglobulin. S100 protein expression is seen focally in many [16]. The lesions predomi- as synaptophysin and
cases. nately present in infants, but chromogranin. Staining for
may occasionally be specific pituitary hormones
Salivary gland anlage tumor is a very rare neoplasm that detected in older children such as prolactin, ACTH,
typically arises on the posterior nasopharyngeal wall or and adolescents. The tumors human growth hormone,
posterior nasal septum [14, 15]. Tumors are usu-ally present most frequently in lutein-izing hormone,
diagnosed in patients less than 3 months of age, with the nasopharynx but may thyroid stimulating
also present in the hormone, and follicle
oropharynx or middle ear stimulating hormone can
and Eustachian tube. also be helpful. Any given
Symptoms are secondary to tumor may express more
local mass effect. The than one pituitary hormone
lesions are grossly polypoid. marker and may be referred
Histologically, they are to as plurihormonal
covered by a dermis with (ectopic) pituitary adenoma,
keratinizing, stratified although a subset may not
squamous epithelium and express any pituitary
append-ages. The hormone markers and are
underlying soft tissue referred to as (ectopic) null
consists of adipose tissue cell pituitary adenomas.
with admixed fibrous tissue.
Mature cartilage and bone Rarely, craniopharyngiomas
may also be present. will present in the naso-
pharynx [18]. Patients are
Pituitary adenomas can also usually younger than 30 years
present as nasopharyn-geal old and will present with
masses, usually through the nonspecific findings,
direct extension of tumor occasionally with visual
from the sella turcica or, problems. The tumors are
rarely, through the composed of nests
Fig. 2  Nasopharyngeal papillary adenocarcinoma: these tumors are
development of tumor from
invariably low grade and composed of delicate arborizing papillae and
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\ Head and Neck Pathol

Fig. 3  Salivary gland anlage

tumor: this tumor appeared
cellular and somewhat nodular
from low power (a). Bland
squamous nests and small cysts
were present admixed with
spindled cells (b) and tubules

(c). Other areas were composed

mostly of bland tubules with
imma-ture epithelial and stromal
elements (d)
rounding tissues. adenomatous cellular stroma
and cords of maturing squamous cells Most, however, polyposis coli gene (Fig. 4). The vessel
that keratinize and have a reticular will behave in a may be involved in wall thickness can
appearance akin to that of benign fashion, the pathogenesis of vary from a single
and only 20% will these tumors [23, layer of
ameloblastoma.
recur after 24]. endothelium to
resection and vessels with
The WHO has changed the terminology even-tually those
from naso-pharyngeal angiofibroma to
Grossly, juvenile multiple layers of
patients will be angiofibromas are smooth muscle
juvenile angiofibroma. Juve-nile cured with more
angiofibromas are tumors of male polypoid and firm that can
surgery. Patients
adolescents [19–22]. They almost [19–22].
with familial
universally arise during the second decade adenomatous Histologically,
of life consistent with the now widely polyposis (FAP) they are
accepted theory that they are androgen have been found to composed of a Fig. 4  Juvenile
dependent. The tumors extend from the be 25 times more rich Angiofibroma: a
posterior lateral nasal wall of the typical case with
likely to have
nasopharynx and often lead to nasal small delicate ves-
nasopharyn-geal network of sels, occasional
obstruction. Epistaxis and nasal drainage angiofibromas than variably sized, larger more muscular
are also typically seen. Nasopharyngeal the general public, irregularly shaped vessels and bland
angiofibromas may sometimes be locally implying that vessels within a spindled stro-mal
aggressive and can extend into sur- mutations of the low to moderately cells

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Head and Neck Pathol\

tumors (i.e.,
appear hyalinized or “pad-like”. The vessels can be throm- 31]. Microscopically, chondrosarcoma). It is
bosed either naturally or, in the case of resected specimens, tumors are composed of typically retained in both
with preoperatively injected material. The stromal tissue is lobules the conventional and
composed mostly of thick and thin fibrils of collagen and can chondroid areas of
appear variably cellular. Numerous oval to spindled to of mucoid material and chordomas but is
stellate stromal cells are arranged haphazardly through-out neoplastic cells separated by diminished in
the lesions. These cells are bland and have a small to fibrous bands. The dedifferentiated areas [36].
moderate amount of eosinophilic cytoplasm and bland oval cellularity varies from
nuclei with fine chromatin and small, indistinct nucleoli. lobule to lob-ule. Tumor Haematolymphoid tumors
Occasional atypical and multinucleated cells can be seen, but cells are arranged singly, in of the nasopharynx include
mitotic figures are rare. The overlying respiratory-type cords or in sheets and are neoplasms of lymphoid,
epithelium can be intact or eroded and, when intact, may suspended in the myxoid plasma cell, or myeloid
undergo squamous metaplasia. Background mast cells are substance. These cells vary origin arising in the
invariably present, often in large numbers. Rarely, these in size and character. They nasopharynx [ 40, 41].
tumors undergo sarcomatous “transformation,” almost range from smaller, more Diffuse large B-cell
invariably after the patients have received radiation therapy plasmacytoid cells with lymphoma is most common,
[25, 26]. little or no cytoplasmic followed by NK/T-cell lym-
vacu-olization to large, phoma and peripheral T-cell
Immunohistochemically, the lesions show non-specific but multivacuolated lymphoma, NOS. Other
expected findings [27]. The endothelial cells react with physalipherous cells. lymphomas are rare and
antibodies to typical endothelial antigens such as CD31, Cellular atypia and mitotic may include MALT
CD34 or factor VIII-related antigen. The focal smooth activity vary from case to lymphoma, follicular
muscle surrounding these vessels typically shows immu- case and some examples lymphoma, Burkitt
noreactivity with antibodies to SMA and can react with show frank anaplasia with lymphoma, and mantle cell
antibodies to desmin. The stromal cells are usually noted to numer-ous mitotic figures. lymphoma and anaplastic
show immunoreactivity only with antibodies to vimen-tin. In some tumors, the myxoid large cell lymphoma. The
Androgen receptors have been identified by immuno- material focally becomes tumors are discussed in
histochemistry in both the stromal and endothelial cells, chondroid and the depth elsewhere.
whereas most cases will show no immunoreactivity with neoplastic cells reside in
antibodies to estrogen or progesterone receptors [28]. Sup- apparent lacunae (chondroid
porting a possible relationship to FAP, nuclear localization of chordoma) [ 31, 38]. Areas
beta-catenin has also been reported [29]. of more obvious
Summary
conventional chordoma are
Chordomas develop along the spinal axis and are believed by usu-ally seen with these
tumors. Rare chordomas are The nasopharynx is home to
some to arise from notochordal remnants [30–34]. The
associ-ated with areas of a limited number of tumor
tumors most often involve the sacrococcygeal areas,
types with nasopharyngeal
although up to one quarter develop at the base of the skull. pleomorphic sarcoma
(dedifferentiated carcinoma being the most
As such, projection into the nasopharynx, nasal cav-ity or
chordoma), usually at the common. In the 4th edition
sinuses occurs in up to a quarter of these cases and the
time of a later recurrence of the WHO Classification
tumors may be sampled through these regions [31, 35].
[36]. of Head and Neck Tumors
there are only minor
Chordomas are more common in men and can develop at any changes in terminology
age. In one large series of tumors involving the spheno- The neoplastic cells of
compared with the 3rd
occipital area, the mean age at presentation was 38 years chordoma are usually
edition.
[31]. Patients with chordomas involving the base of the skull immu-noreactive with
frequently present with diplopia or other vis-ual defects. The antibodies to cytokeratins, Compliance with Ethical
tumors are notoriously difficult to resect in their entirety and EMA, S100 protein, Standards
frequently can recur, eventually lead-ing to the death of their brachyury and vimentin
patients. Children with chordomas fare somewhat better, [33 , 38, 39]. This unique
Conflict of interest Drs. Wenig
while patients with dedifferentia-tion within their tumors fare immunoreactivity helps and Stelow have no conflict of
considerably worse [32, 36]. Newer treatments using proton distinguish chordoma from inter-est.
beam therapy, allow for increased radiation doses to the both epithelial
tumor while reducing doses to surrounding tissues [37]. malignancies, such as Human and Animal
mucinous carcinomas and Participants This article does
mesenchymal neoplasms, not contain any studies with
Grossly, chordomas are lobulated and gelatinous [30, human participants or animals
especially cartilaginous
performed by any of the authors.
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\ Head and Neck Pathol

Rosai J. Salivary-gland anlage 1993;105:1550–2.

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