诊断

Review

Review of the histological classification of nasopharyngeal carcinoma

Zhi Li1, Yong-sheng Zong1

1Department 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:image001.gif2014 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

International NPC histological classification

Liang’s classification (1961) [43]

Norms of China for NPC (1991) [45]

2001 classification (2001) [46]

WHO classification (1991) [25]

WHO classification (2005) [1]

1. Well-differentiated type

1. Carcinoma in situ

1. Keratinizing squamous cell carcinoma

1. Keratinizing squamous cell carcinoma

1. Keratinizing squamous cell carcinoma

Squamous cell carcinoma grade I

2. Invasive carcinoma

Well-differentiated

Well-differentiated

Well-differentiated

Squamous cell carcinoma grade II

Microinvasive carcinoma

Moderately-differentiated

Moderately-differentiated

Moderately-differentiated

Basal cell carcinoma

Squamous cell carcinoma

Poorly differentiated

Poorly differentiated

Poorly differentiated

Columnar cell carcinoma (adenocarcinoma)

Well-differentiated

2. Non-keratinizing carcinoma

2. Non-keratinizing carcinoma

2. Non-keratinizing carcinoma

2. Poorly-differentiated type

Moderately-differentiated  Poorly-differentiated

Differentiated type

Differentiated type

Differentiated type

Large round cell carcinoma

Adenocarcinoma

Undifferentiated type

Undifferentiated type

Undifferentiated type

Spindle cell carcinoma Squamous cell carcinoma grade III

Vesicular nucleus cell carcinoma

Mixed types

 

3. Basaloid squamous cell carcinoma

3. Undifferentiated type Pleomorphic cell carcinoma

Undifferentiated carcinoma

3. Adenocarcinoma

Traditional type

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, Liang’s 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 Liang’s 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. Müller 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.

 

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