Review of the histological classification of nasopharyngeal carcinoma

Zhi Li1, Yong-sheng Zong1

1
Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University 58, Zhongshan

Road II, Guangzhou 510080, Guangdong, China

Corresponding author: Zhi Li, Email: lizhi@mail.sysu.edu.cn

Citation: Li Z, Zong YS. Review of the histological classification of nasopharyngeal carcinoma.

J Nasopharyng Carcinoma, 2014, 1(15): e15. doi:10.15383/jnpc.15.

Competing interests:The authors have declared that no competing interests exist.

Conflict of interest: None.

Copyright: 2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is

an open-access article distributed under the terms of the Creative Commons Attribution License,

which permits unrestricted use, distribution, and reproduction in any medium, provided the

original author and source are credited.

Abstract: Nasopharyngeal carcinoma (NPC) is a tumor arising from the epithelial cells that

cover the surface and line the nasopharynx. Regardless of geographic distribution, racial

background and enigmatic etiology of NPC, A major problem has been the lack of a universally
accepted system for histopathologic classification of NPC. To alleviate this problem, the World

Health Organization (WHO) advocated a classification using the diagnostic designation of

keratinizing squamous cell carcinoma and nonkeratinizing carcinoma since 1978, although this

classification system has not been accepted worldwide. During the past 50 years, several NPC

histological classifications have been published and adopted in clinic. As a high-incidence area

of NPC, until new classification published in 2001, Chinese NPC classifications can not be very

well to link with the international classifications of NPC, which makes great misunderstandings

in international communication. Actually there is still a long way to go to reach the consensus on

histological classification of NPC. This review will retrospectively link the difference of these

systems.

Keywords: Nasopharyngeal carcinoma; Histological classification; Differentiation; Correlation

Introduction

Nasopharyngeal carcinoma (NPC) is a unique carcinoma arising in the nasopharyngeal mucosa

that showing light microscopic or ultrastructural evidence of squamous differentiation.

Regardless of geographic distribution, racial background and enigmatic etiology of NPC, a major

problem has been the lack of a universally accepted system for histopathologic classification of

NPC. Although World Health Organization (WHO) advocates its diagnostic designation, there

have several histological classification systems been used to identify the variants of NPC in high-

and low-incidence regions. According to the WHO classification, NPC encompasses squamous
cell carcinoma, non-keratinizing carcinoma and basaloid squamous cell carcinoma. The non-

keratinizing type is further subdivided into differentiated and undifferentiated [1]. Therefore, this

strict definition of NPC by WHO is to the exclusion of all other malignant tumors that may arise

in nasopharyngeal region, such as adenocarcinomas, salivary gland-type carcinomas, sarcomas

and lymphomas. However, before the criteria of WHO classification system is accepted in the

worldwide, there is still a long way to go to reach the consensus on histological classification of

NPC. In fact, Chinese classification system of NPC has not completely unified to WHO system.

This review will retrospectively link the difference of these systems.

Histology of nasopharynx and histogenesis of NPC

The nasopharynx is the narrow tubular passage behind the nasal cavity. Its sloping roof and

posterior wall are formed by the basi-sphenoid, basi-occiput and the first cervical vertebra.

Anteriorly, it communicates with the nasal cavity via the choanae. The orifices of Eustachian

tubes are in the lateral walls, and each is shielded superiorly and posteriorly by a comma-shaped

elevation called the torus tubarius. Immediately above and behind the torus tubarius is a

pharyngeal recess called the fossa of Rosenmuller. The nasopharynx tapers inferiorly, and

continues as the oropharynx from the level of the soft palate. The nasopharynx constitutes part of

the Waldeyer ring. Histologically, its mucosa is covered by respiratory-type ciliated epithelium,

but variable amounts of squamous epithelium are common. The mucosa exhibits invaginations,

forming crypts that abut the underlying stroma. The stroma is rich in lymphoid tissue that often

includes reactive lymphoid follicles. The surface or crypt epithelium is commonly infiltrated by

many small lymphoid cells, which expand and disrupt the epithelium to produce a reticulated
pattern. Some seromucinous glands are present, but they are not as abundant as in the nasal

mucosa. The most frequent site of origin for NPC is the lateral wall of the nasopharynx, an area

abundant in respiratory epithelium. Adjacent squamous epithelium joins the respiratory

epithelium via an intervening intermediate epithelium which has ultrastructural properties similar

to those of respiratory epithelium. In embryonic development, respiratory epithelium precedes

the development of squamous epithelium in the nasopharynx [2, 3].

The histogenesis NPC has been a complex problem. The ultrastructural studies of Svoboda et al

in 1965 proposed a squamous cell origin for NPC based on the ultrastructural demonstration of

desmosomes and keratin fibrils (tonofilaments) [4]. The subsequent studies have supported this

concept and have postulated to classify all NPCs as variants of squamous cell carcinoma [5-6].

However, some studies, including ultrastructural data from Chinese NPC patients, have

suggested the possibility of a respiratory epithelial origin for NPC based on ultrastructural

studies showing common cellular organelles in normal respiratory epithelium and some NPC

tumor cells [7-10]. Lin and his colleagues showed that some NPC cells contained a cytoplasmic

vacuolar system with a well-developed Golgi complex and endoplasmic reticulum as well as

cytoplasmic tonofilaments. They proposed that NPC, at least some variant of NPC, might arise

from basal cells of respiratory epithelium [11]. Sichuan Medical College in China have

recognized 6 morphologic types of NPC cells based on ultrastructural findings: Type 1 and 2

contain abundant tonofilaments and desmosomes; Type 4 and 5 contain secretory vacuoles and

rough endoplasmic reticulum; Type 3 contains mixtures of types 1, 2, 4, and 5; however, Type 6

are poorly differentiated with very few organelles. According to the ultrastructural variability of

NPC cells, they suggest that perhaps at least some cases of NPC are in a state of differentiation

toward respiratory epithelium because there are some similarities between NPC cells and
respiratory epithelial cells [8]. Prasad suggests that NPC cells may be derived from epithelial

cells that have undergone metaplastic transformation from columnar (i.e., respiratory) to

squamous cells because his ultrastructural study reveals secretory granules, well-developed

Golgi complex, and granular endoplasmic reticulum appear to have intermingle with

tonofilaments and desmosomes in cytoplasm of NPC cells [12]. Batsakis and his colleagues

propose that undifferentiated or nonkeratinizing NPC arises from primitive stem cells or

indeterminate cells, or from intermediate epithelium, all of these cell types being capable of

differentiating into mature squamous or respiratory epithelium [13]. Shi et al. found that some

cases of NPC showed carcinoma in situ involving a respiratory epithelial mucosal surface, and

showed immunohistochemical staining properties reminiscent of those of respiratory epithelium.

Their immunohistochemical study on NPC suggests that perhaps some non-keratinizing and

undifferentiated cases of NPC have a respiratory epithelial origin, although some squamous

morphologic ultrastructural features may be present [14]. At present, the histogenesis of NPC

remains unknown, although a consensus of the surface or crypt epithelium of nasopharyngeal

mucosa origin has been proposed [1]. However, some researches on precursor lesions of NPC,

including dysplasia and carcinoma in-situ of nasopharyngeal mucosa, suggest that most NPCs do

not originate from NPC in-situ because an in-situ or intraepithelial component is rarely detected

in NPC [15-17]. Presumably, NPC derives from precursor cells in basal layers of the stratified

squamous epithelium, a finding further supported by the strong immunoreactivity for p63 in both

the tumor and normal basal cells. These progenitor cells appear to be multipotent and capable to

differentiate toward both columnar and squamous phenotype.

International histological classification of NPC

NPC was firstly described as skull base cancer in 1845 by Michaux (another argument was in

1837 by Derand-Fardel) [18-19]. In 1921, NPC was firstly classified as a separate entity and

designated as lymphoepithelioma by Regaud and Schmincke [20-21]. They proposed this

tumor might originate from lymphoepithelium. Quick and Culter in 1927 put forward the name

of transitional cell carcinoma. In 1938, Cappell divided NPC into Schimincke type

lymphoepithelioma and Regaud type lymphoepithelioma. In 1967, the NPC symposium of UICC

(Union for International Cancer Control) classified NPC into 7 subtypes: classic epidermoid

carcinoma, clear cell carcinoma, spindle cell carcinoma, transitional cell carcinoma,

lymphoepithelial carcinoma, pleomorphic carcinoma and mixed cell carcinoma.

Shanmugaratnam divided NPC histopathology into two major types: squamous cell carcinoma

and undifferentiated carcinoma. Squamous cell carcinoma subdivided into classic carcinoma,

clear cell carcinoma and spindle cell carcinoma; undifferentiated carcinoma included vesicular

nucleus cell carcinoma, fused type and mixed type [22]. In 1978, the first edition of WHO

classification of tumors published its NPC histological classification, the tumor was divided into

three major types: type I (squamous cell carcinoma), type II (non-keratinizing carcinoma) and

type III (undifferentiated carcinoma) [23]. However, in 1982, WHO regional offices for the

western pacific suggested that WHO type II and type III NPC should be combined, and only

type I and type III NPC retained. In addition, WHO define the abbreviation of NPC was only

applicable for the nasopharyngeal cancer with squamous differentiation under the light

microscope [24]. It means that NPC did not include the cancers occurring in the nasopharynx

but without squamous differentiation such as adenocarcinoma, salivary gland-type carcinomas,

sarcomas and lymphomas. In 1991, the second edition of WHO classification of tumors revised
its NPC histological types. There were two main groups according to whether or not there is

clear evidence of squamous differentiation by light microscopy. One was squamous cell

carcinoma (keratinizing squamous cell carcinoma), the other was non-keratinizing carcinoma.

The latter was subdivided into differentiated and undifferentiated variants [25]. In this

classification, the keratinizing squamous cell carcinoma of type I in 1978 WHO classification

was retained as squamous cell carcinoma, while part of type I (non-keratinizing squamous cell

carcinoma), type II and III variants of 1978 WHO classification were included as non-

keratinizing carcinoma. Based on the second edition of WHO classification of NPC, in 2005,

WHO updated its NPC histological classification and basaloid squamous cell carcinoma was

firstly added into the NPC histological classification (Table 1) [1].

Table 1. The main NPC histological classifications of Chinese and international system.

Chinese NPC histological classification Interna

Liangs classification (1961) [43] Norms of China for NPC (1991) [45] 2001 classification (2001) [46] WHO classification

1. Keratinizing squamous cell 1. Keratinizing squ

1. Well-differentiated type 1. Carcinoma in situ
carcinoma carcinom

Squamous cell carcinoma grade I 2. Invasive carcinoma Well-differentiated Well-differ

Squamous cell carcinoma grade

Microinvasive carcinoma Moderately-differentiated Moderately-di
II
 Basal cell carcinoma Squamous cell carcinoma Poorly differentiated Poorly diffe

Columnar cell carcinoma

Well-differentiated 2. Non-keratinizing carcinoma 2. Non-keratinizing
(adenocarcinoma)

Moderately-differentiated
2. Poorly-differentiated type Differentiated type Differentia
Poorly-differentiated

Large round cell carcinoma Adenocarcinoma Undifferentiated type Undifferenti

Spindle cell carcinoma

Squamous cell carcinoma grade Vesicular nucleus cell carcinoma Mixed types

III

3. Adenocarcinoma

3. Undifferentiated type Pleomorphic

Undifferentiated carcinoma Traditional type
cell carcinoma

Salivary-gland type

4. Carcinoma in situ and

microinvasive carcinoma

Squamous cell type

Columnar cell type

Keratinizing squamous cell carcinoma

This variant of NPC is an invasive carcinoma showing obvious squamous differentiation at the

light microscopic level, in the form of intercellular bridges and /or keratinisation over most of the

tumor, morphologically similar to keratinizing squamous cell carcinoma occurring in other head

and neck mucosal sites. The degree of differentiation can be further graded as: well

differentiated, moderately differentiated and poorly differentiated. The tumor cell borders are

distinct and separated by intercellular bridges. The nuclei often show hyperchromasia, but not

vesicular pattern, and the degree of nuclear pleomorphism ranges from mild to marked. The

tumor contains desmoplastic stroma infiltrated by variable numbers of lymphocytes, plasma

cells, neutrophils and eosinophils. Compared with non-keratinizing carcinoma, this variant of

NPC shows a greater propensity for locally advanced tumor growth and lower propensity for

lymph node metastasis. Some studies suggest that this subtype of NPC has lower responsiveness

to radiation therapy and a worse prognosis [26-28]. However, other studies have not found this

subtype to differ in biological behavior [29-30].

The frequency of keratinizing squamous cell carcinoma of NPC is varied. In high incidence

areas, such as southern China, only 1%-2% of NPC patients are this tumor histology, while the

corresponding histological distribution in low incidence areas (Japan and North America) is

13%-25% [1, 31-32]. However, Singapore shows this histological type in 17% of NPC patients,

although it is also in high incidence area [28]. Unlike non-keratinizing carcinoma, keratinizing

squamous cell carcinoma of NPC tend to carry lower copy numbers of EBV, and nuclear signals

of EBER are usually confines to the less differentiated cells (basal cells that surround the
individual tumour islands), but not in the cells showing obvious squamous differentiation on in

situ hybridization [33].

Non-keratinizing carcinoma

Non-keratinizing carcinoma of NPC comprises over 95% of NPC in high incidence areas and

approximately 75%-87% of NPC in low incidence areas [1, 31-32]. These tumors are generally

more radiosensitive than squamous cell carcinoma and have stronger relationships with EBV

[34-36]. The tumors are often infiltrated by abundant lymphocytes. This group comprises a

differentiated type of non-keratinizing carcinoma and an undifferentiated type. However,

subclassification is optional, since their distinction is of no clinical or prognostic significance,

and different areas of the same tumor or different biopsies taken at different time intervals from

the same patient may exhibit features of one or the other subtype. When both subtypes are seen

in a specimen, the tumor may be classified according to the prominent subtype, or as non-

keratinizing carcinoma with features of both subtypes.

The undifferentiated subtype is characterized by syncytial-appearing large tumour cells with

indistinct cell borders, round to oval vesicular nuclei, and large central nucleoli. The cells often

appear crowded or even overlapping. The scant cytoplasm is either amphophilic or eosinophilic.

Abundant lymphocytes and plasma cells infiltrate the tumor islands, breaking them up into tiny

clusters or single cells and obscuring the epithelial nature of the tumor; the term

lymphoepithelial carcinoma may be applied for such cases. There can be small foci of

primitive squamous differentiation in this subtype. The undifferentiated type of NPC represents

over 90% of all NPCs in high incidence areas, and is the most frequent tumor type seen in

pediatric age groups [37].

The differentiated subtype differs from the undifferentiated subtype in showing cellular

stratification and pavementing, often with a plexiform growth, reminiscent of transitional cell

carcinoma of the bladder. The tumor cells show fairly well-defined cell borders and sometimes

vague intercellular bridges, and there may exceptionally be occasional keratinized cells.

Compared with the undifferentiated subtype, the cells are often slightly smaller, the nuclear-

cytoplasmic ratio is lower, the nuclei can be more chromatin-rich, and nucleoli are usually not as

prominent. This type of NPC is uncommon, representing approximately 7%-12% of all NPCs in

southern China [1]. However, it is almost equal to undifferentiated type in Singapore with

approximately 41% of NPC patients [28].

Basaloid squamous cell carcinoma

Only a few cases of primary basaloid squamous cell carcinoma of NPC have been described in

literature [38-41] and represent less than 0.2% of all NPCs in southern China [1]. The

morphological features of this type are identical to the same tumor more commonly occurring in

other head and neck sites. Basaloid cells are small, with hyperchromatic nuclei without nucleoli,

and scant cytoplasm. They are closely packed, growing in a solid pattern with a lobular

configuration, and in some cases, there is prominent peripheral palisading. Comedo-type necrosis

and distinctive small cystic spaces containing PAS- and Alcian blue positive material can be

found in this type of NPC. The tumor appears to show a lower clinical aggressiveness compared

with basaloid squamous cell carcinoma occurring in other head and neck sites. The tumor cells of

this type in all Asian reported cases were positive to EBV, while only one Caucasian case was

negative [39, 41].

Chinese histological classification of NPC

In 1940s, lymphoepithelial carcinoma was used to describe this malignant tumor in China.

Since 1950s, some Chinese pathological experts have published a number of research papers

about NPC histological classification [42]. Department of pathology of Zhongshan Medical

College divided NPC into 4 types: squamous cell carcinoma, transitional cell carcinoma,

lymphoepithelial carcinoma and adenocarcinoma in 1961. In the same year, Liangs

classification of NPC proposed three main groups according to their histological characteristics

and biological behaviors, which were well-differentiated, poorly-differentiated and

undifferentiated types. Well-differentiated type included squamous cell carcinoma grade I and II,

basal cell carcinoma and columnar cell carcinoma (adenocarcinoma). Poorly-differentiated type

included large round cell carcinoma, spindle cell carcinoma and squamous cell carcinoma grade

III. Undifferentiated type was pleomorphic cell carcinoma [43]. This histological classification

had a profound impact on subsequent classification of NPC in China. In 1979, the 5th Meeting of

Chinese NPC Prevention Collaboration held in Changsha city, China. Two classification strategy

of NPC were proposed in this meeting. Strategy I divided NPC into two groups: carcinoma in

situ and invasive carcinoma. Invasive carcinoma subdivided into 4 subtypes, which were

vesicular nucleus cell carcinoma (also known as large round cell carcinoma or lymphoepithelial

carcinoma), squamous cell carcinoma (the degree of differentiation was further graded as well-

differentiated and poorly differentiated), undifferentiated carcinoma and other rare carcinoma

such as adenoid cystic carcinoma, basal cell carcinoma and mucoepidermoid carcinoma. Strategy

II had also two main groups as strategy I: carcinoma in situ and invasive carcinoma. However,

invasive carcinoma subdivided as 4 subtypes: well-differentiated carcinoma including well-

differentiated squamous cell carcinoma and adenocarcinoma; poorly differentiated carcinoma

including poorly-differentiated squamous cell carcinoma, vesicular nucleus cell carcinoma and

poorly-differentiated adenocarcinoma; undifferentiated carcinoma, and other rare carcinoma

[44].

In 1991, the Norms of China Common Cancer Clinical Diagnosis and Treatment was published,

and NPC was formally divided into carcinoma in situ and invasive carcinoma as two major

groups. Invasive carcinoma was sub-divided into micro-invasive carcinoma, squamous cell

carcinoma, adenocarcinoma, vesicular nucleus cell carcinoma and undifferentiated carcinoma.

Squamous cell carcinoma and adenocarcinoma included well-differentiated, moderately-

differentiated and poorly-differentiated subtypes [45]. Like previously proposed Chinese NPC

classification, this classification had also accepted adenocarcinoma as an independent entity of

NPC, which was not consistent with NPC histological classification recommended by WHO. In

addition, vesicular nucleus cell carcinoma was also identified as an independent entity of NPC

rather than a histological pattern of undifferentiated carcinoma. This classification has been

advocated widely and still being in use in China. However, there are great differences between

1991 Chinese and international (WHO) classification. The misunderstandings in communication

are frequently because of different NPC classification system. Therefore, in 2001, Zong and his

colleagues proposed a new histological classification of NPC to bring Chinese classification

in line with international standard [46]. In the new 2001 Chinese classification of NPC, four

main groups were categorized, which were keratinizing squamous cell carcinoma, non-

keratinizing carcinoma, nasopharyngeal adenocarcinoma and carcinoma in situ/microinvasive

carcinoma. According to the degree of tumor differentiation, keratinizing squamous cell

carcinoma was further graded as well-differentiated, moderately-differentiated and poorly

differentiated types. Anaplastic squamous cell carcinoma, clear-cell squamous cell carcinoma,
pseudoglandular squamous cell carcinoma, papillary squamous cell carcinoma and basaloid

squamous cell carcinoma could be regarded as the specific histological patterns of keratinizing

squamous cell carcinoma with various degree of differentiation. Non-keratinizing carcinoma was

subdivided into differentiated, undifferentiated and mixed types. The histological diagnostic

criteria of these subtypes are similar to those in 1991 WHO classification of NPC. Mixed type of

non-keratinizing carcinoma was not included in WHO classification. Zong et al. identified this

type when the tumor exhibit features of both differentiated and undifferentiated type. However,

the authors considered that the mixed type of NPC might be combined with undifferentiated type

because they exhibited similarities in tumor biological behaviors [46]. Nasopharyngeal

adenocarcinoma had two subtypes, traditional adenocarcinoma and salivary-gland type

adenocarcinoma. Adenocarcinoma with focal squamous metaplasia, adenosquamous carcinoma,

papillary adenocarcinoma, intestinal-type adenocarcinoma and signet ring cell carcinoma were

regarded as histological pattern of traditional adenocarcinoma, while adenoid cystic carcinoma

and mucoepidermoid carcinoma were the most common tumors of salivary-gland type

adenocarcinoma. In fact, except for nasopharyngeal adenocarcinoma and carcinoma in

situ/microinvasive carcinoma variants, 2001 Chinese histological classification of NPC was

almost consistent with 1991 WHO classification.

The main disagreement of NPC histological classification between Chinese and

international classification system

Whether or not carcinoma in situ and microinvasive carcinoma should be identified as distinct

variants of NPC in histological classification?

In 1991 and 2001 Chinese NPC classification, nasopharyngeal carcinoma in situ and

microinvasive carcinoma were proposed as variants of NPC. By definition, pure nasopharyngeal

carcinoma in situ is characterized by atypical epithelial change confined to the surface or crypt

epithelium, and lacking an invasive component. The epithelium is usually slightly thickened, and

consists of cells with variable loss of polarity, nuclear enlargement, nuclear crowding and distinct

nucleoli. 2001 Chinese classification further subdivided nasopharyngeal carcinoma in situ into

squamous cell type and columnar cell type according to the different type of epithelium

undergoing carcinogenesis [46]. Squamous cell carcinoma in situ was often observed at the

lining epithelium of nasopharynx, while columnar cell carcinoma in situ usually located at the

mucosa of crypts. However, in clinical practice, an in-situ or intraepithelial component is

identified in only 3-8% of NPC cases, and pure nasopharyngeal carcinoma in situ, as confirmed

by multiple biopsies to rule out an invasive component, is very rare. Therefore, when

microscopical foci of nasopharyngeal carcinoma in situ in biopsies, it is often difficult to

determine whether the invasive carcinoma has already existed at the other sites of

nasopharyngeal tissues. So far, all cases of nasopharyngeal carcinoma in situ studied have been

positive for EBV (EBER), confirming that EBV infection precedes the acquisition of

invasiveness by nasopharyngeal carcinoma. EBER may aid in the distinction between carcinoma

in situ and non-specific reactive atypia of the nasopharyngeal epithelium. Therefore, a few

studies suggest that pre-invasive NPC should be regarded as a rare but distinct entity [47-48],

and indeed a proportion of patients develop invasive cancer on follow-up [49]. At present, WHO

NPC classification has accepted the carcinoma in situ as a precursor lesion, but not a variant of

NPC [1]. Since nasopharyngeal carcinoma in situ has reliably identified histological appearances

and relevance for clinical outcome, we consider it should be classified as a distinct variant of
NPC, but not as a precursor lesion only, although it is indeed rare to be observed in clinical

practice.

The nasopharyngeal microinvasive carcinoma is designed when the tumor cells break the

basement membrane and infiltrate into the stroma, the extension of invasive cells is no more than

one high power field (under the objective 40 times) in 1991 and 2001 Chinese NPC classification

[45-46]. Microinvasive carcinoma is infrequent and commonly low-diagnosed because invasive

carcinoma is often observed in other fields of microscopy or other biopsies of nasopharynx in

same patient. In fact, WHO has not described this lesion in NPC classification, and to our best

knowledge, so far microinvasive nasopharyngeal carcinoma has only described and discussed in

Chinese literature [46, 50]. Like nasopharyngeal carcinoma in situ, microinvasive carcinoma

may be difficult to be ascertained in the biopsies of nasopharynx. Zong suggested that

microinvasive carcinoma is frequently associated with carcinoma in situ [46]. However, when

microinvasive carcinomas have been rarely encountered in the absence of an adjacent in situ

component, the diagnosis becomes challenging and puzzled. In addition, we found that there

were one or more separated microscopic foci of infiltration of tumor cells into the

nasopharyngeal stroma when microinvasive carcinoma occurred. It is difficult to determine

whether or not the extension of infiltrating tumor cells is beyond the specialized fields under the

microscopy. Therefore, we suggest that the criteria for microinvasive carcinoma may be defined

when the greatest dimension in any one invasive focus is less than or equal to 1mm in size. Since

only a few of studies on nasopharyngeal microinvasive carcinoma are investigated, reliable data

on the clinical behavior of microinvasive carcinoma are not available and no predictive factors

have been identified. At present, microinvasive carcinoma can not be regarded as a distinct

variant of NPC. However, this lesion should be added into the NPC classification if the
prognoses of patients with microinvasive carcinoma have been convinced to be more excellent

than that in patients with invasive carcinoma. Of course, it is necessary that the strict definition

of microinvasive carcinoma is applied for diagnosis and this lesion can be clearly recognized

firstly.

Whether or not basaloid squamous cell carcinoma is a distinct variant of NPC or a histological

pattern of differentiation of keratinizing squamous cell carcinoma

In 1961 Liangs classification, 1991 and 2001 Chinese classification, basaloid squamous cell

carcinoma was regarded as a histological pattern of squamous cell carcinoma or keratinizing

squamous cell carcinoma. In Chinese classification, histological patterns of differentiation are

considered identifiable histological appearances, but that do not have a distinct clinical or

pathological significance. However, since 2005, basaloid squamous cell carcinoma has been

accepted as a distinct variant of NPC by international classification because of its distinctive

morphology, age distribution and biologic behaviour. The tumour appears to show a lower

clinical aggressiveness compared with basaloid squamous cell carcinoma occurring in other head

and neck sites. Basaloid squamous cell carcinoma has been accepted as a variant of squamous

cell carcinoma in other head and neck sites. But it is seldom paid attention in nasopharynx

because nasopharyngeal basaloid squamous cell carcinoma is rare, to our knowledge, so far only

6 such cases have been described in literature [38-41]. In fact, the association between this type

of tumor and its clinical behaviours has not been established yet. Mller and his colleagues have

summarized the characteristics of the nasopharyngeal basaloid squamous cell carcinoma as

follow: (1). younger median age at diagnosis as for other nasopharyngeal carcinomas; (2). very

slow development before diagnosis; (3). other etiological factors than nicotine and alcohol abuse
may play a role in oncogenesis; (4). presence of Epstein-Barr virus seems not to be correlated

with the basaloid squamous cell carcinoma of the nasopharynx; (5). possibly lower

aggressiveness than the tumor in other sites; (6). radical surgical and radiation therapy may

control the tumour [39]. Therefore, there are some differences between basaloid squamous cell

carcinoma and keratinizing squamous cell carcinoma of nasopharynx. Respecting these

differences, we consider that particular attention must be paid to find the correlation between this

variant and its clinical observation, including prognosis and optimum treatment strategy. Once

nasopharyngeal basaloid squamous cell carcinoma has been convinced to have identifiable

clinical and pathological significance, it will be accepted as a distinct variant of NPC by Chinese

classification although it is extremely rare in clinical practice.

Should nasopharyngeal adenocarcinoma be added into the NPC histological classification?

Unlike international classification, Chinese NPC classification always regards nasopharyngeal

adenocarcinoma (NAC) as a clearly distinct variant of NPC, which might originates from the

lining epithelium or crypt, as well as small salivary glands of nasopharynx [43-46]. In 2001

Chinese classification, NAC was first classified into traditional (conventional) adenocarcinomas

and salivary gland-type adenocarcinomas. The traditional type was further subdivided into acinar

adenocarcinoma, papillary adenocarcinoma and tubular adenocarcinomas. Salivary gland-type

adenocarcinomas include adenoid cystic adenocarcinoma, mucoepidermoid adenocarcinoma and

malignant mixed tumor. However, adenocarcinomas have been excluded by 1991 and 2005

WHO classification, in which nasopharyngeal papillary adenocarcinoma and salivary gland-type

carcinoma are low-grade carcinomas of nasopharynx with distinctive characteristics from NPC

in their morphology and epidemiology [1, 25].

Besides the distinctive morphological features, there are some main difference between NAC and

NPC. (i) NPC has a unique geographical distribution, particularly in the Cantonese population of

China. In endemic areas, the undifferentiated non-keratinizing carcinoma accounts for more than

95%. In low incidence areas, keratinizing differentiated squamous cell carcinoma and

differentiated non-keratinizing carcinoma accounts for 25 and 12%, respectively. The

undifferentiated non-keratinizing carcinoma accounts for no more than 65%. However, the

geographical distribution of NAC is not distinct. The recent studies reveal that the incidence of

NAC of all cancers of nasopharynx is 0.11% in southern china, 0.38% in Hong Kong, 1.3% in

Taiwan, 0.7% in Italy, 0.0% in Uganda and 3.9% in USA [51-55]. These data suggest that the

incidence of NAC is extremely rare even among defined ethnic groups, and there is no specific

geographical distribution [56-57]. (ii) Epstein-Barr virus (EBV) may not be closely associated

with the carcinogenesis of NAC. A unique feature of NPC is its strong association with EBV.

Higher EBV antibody titers, especially of IgA class, are observed in most NPC patients. Latent

EBV infection is identified in cancer cells of virtually all cases of NPC in endemic regions.

Almost all of NPC cases have EBER positive by in situ hybridization (ISH). However, the

positive rate for the EBV antibody VCA-IgA in all types of NAC was 53% and only 24% in

the salivary gland type of NPAC [58]. More than 95% of conventional adenocarcinomas show no

EBV infection by EBER detection [46]. But some research data showed EBV was detected by

EBER ISH in 60% cases of salivary gland adenocarcinoma [52]. The prevalence of EA-IgA,

VCA-IgA and EBV DNase antibody plasma level were 13.3%, 25% and 42.9%, respectively in

adenoid cystic adenocarcinoma of the nasopharynx [59]. Due to its rarity, the relationship

between NAC and EBV is still unclear. (iii) Difference in clinical manifestation and prognosis.

The male to female ratio for NAC was reported to be 1.18:1, while the male to female ratio was
reported to be 2-3:1 in NPC. The majority of NPCs arise in the lateral walls, metastasis is

frequently found, and cervical lymphadenopathy is often the only clinical manifestation of NPC

patients. However, the slow rate of growth of NAC might be explained by the long duration of

symptoms before patients sought medical attention. Neck masses are uncommon in NAC due to

its low rate of cervical node metastasis. Due to the rarity of NAC, there is still no standard

treatment. Surgical excision is the treatment choice and radiotherapy is recommended as a

postoperative treatment for patients who are at high risk of postoperative recurrence. But in high-

incidence endemic regions, the treatment of most NAC is similar to that of NPC. It is found that

NAC can be well controlled by radiotherapy with and without chemotherapy. Some research data

reveal that polymorphic low-grade adenocarcinomas, hyalinizing clear cell carcinomas and

acinic cell carcinomas in NAC has good prognosis [60]. Since NPC is highly radiosensitive,

radiotherapy has always been the main treatment of choice for this cancer. With conventional

practice and two-dimensional planning techniques, the local control rates were in the order of

80%, taking all T stages together. Intensity-modulated radiotherapy (IMRT) provides superior

local control and better delineation of tumor target volume [61]. Although overall survival after

radiotherapy for early staging is encouraging, there are significant rates of local failure and

distant metastases subsequent to radiotherapy in the advanced stage disease.

Compared with NPC, NAC is very rare but distinct entity with various pathological types,

clinical manifestation and biological behaviours. We consider that NAC should not be regarded

as a variant of NPC. A slowly rate of growth, a tendency for cranial nerve invasion, a high

recurrence rate and a low distant metastatic rate are characteristic of NAC. Therefore, the clinical

tumor, node and metastases (TNM) staging system for NAC and optimal treatment strategies of

NAC should be established as quickly as possible.

How to link the 1991 Chinese NPC classification with the 1991 and 2005 WHO classification

In 1991, Chinese NPC histological classification was published by the Norms of China Common

Cancer Clinical Diagnosis and Treatment. The invasive carcinoma was divided into micro-

invasive carcinoma, squamous cell carcinoma, adenocarcinoma, vesicular nucleus cell carcinoma

and undifferentiated carcinoma. Squamous cell carcinoma and adenocarcinoma included well-

differentiated, moderately-differentiated and poorly-differentiated subtypes. However, in the

same year, WHO classification divided NPC into keratinizing squamous cell carcinoma and non-

keratinizing carcinoma, the latter was sub-divided into differentiated type and undifferentiated

type. There are some questions when linking these two classifications of NPC. Which

pathological type in Chinese classification on earth corresponding to differentiated or

undifferentiated type of WHO classification was puzzled. It was also confusion whether or not

vesicular nucleus cell carcinoma was an independent variant of NPC. Wu et al considered

undifferentiated carcinoma could be divided into four subtypes according to its morphological

features, which were: 1) Vesicular nucleus cell carcinoma; 2) Undifferentiated carcinoma; 3)

Poorly-differentiated squamous cell carcinoma; 4) Mixture of vesicular nucleus cell carcinoma

and squamous cell carcinoma respectively [62]. Zong et al. revised their classification in 2001

and also considered the vesicular nucleus cell carcinoma or large round cell carcinoma was

essentially a type of undifferentiated carcinoma [46]. Therefore, undifferentiated carcinoma in

1991 WHO classification should included undifferentiated carcinoma, large round cell

carcinoma, vesicular nucleus cell carcinoma, and part of poorly-differentiated squamous

carcinoma in 1991 China classifications. Because the proportion of differentiated non-

keratinizing carcinoma would exceed 90%, and the proportion of undifferentiated carcinoma

would be greatly reduced, if all poorly-differentiated squamous cell carcinoma in 1991 China
classification were included in the differentiated non-keratinizing carcinoma of 1991 WHO

classification, which was obviously inconsistent with the geographical distribution. However, it

need further evaluate which part of poorly-differentiated squamous carcinoma should be

included into the differentiated or undifferentiated non-keratinizing carcinoma.

Conclusion

Review the histological classification of NPC is important for pathologists to understand the

development history of NPC histological research. During the past 50 years, several NPC

histological classifications have been published and adopted in clinic. However, a major problem

at present is still a lack of a universally accepted system for using worldwide. As a high-

incidence area of NPC, until 2001 Chinese classification published, Chinese NPC classifications

can not be very well to link with the international classifications of NPC, which makes great

misunderstandings in international communication. Another important question is the

histological criteria to date for separating the different variants of NPC is based on cellular

morphology and growth patterns. Possibly this separation are not clinically meaningful. To date,

TNM staging system has been proven to be useful for predicting the prognosis of NPC patients.

However, the values of histological classification of NPC for predicting prognosis and

monitoring disease progression, including WHO and Chinese classification, are rather limited. In

most NPC studies, there are no correlation between histological classification and the patients

outcomes. Therefore, the future widely accepted NPC classification should meet the

morphological and clinical conditions simultaneously.