Nasopharyngeal Carcinoma Nonkeratinizing Reticulated

Fig. 2.11 Nasopharyngeal nonkeratinizing carcinoma with papillary architecture. A The tumour forms exophytic papillae with fibrovascular cores. B The lining cells show features of differentiated nonkeratinizing carcinoma.

plasmic clear cell change, but this is such an uncommon feature that the alternative diagnosis of lymphoma or salivary gland-type carcinoma should always be considered. Exceptionally, there is accumulation of extracellular edema fluid or mucosubstance, breaking up the tumour islands to produce a complex reticulated pattern. Nasopharyngeal carcinoma may contain intracytoplasmic mucin in very rare cells. It has also rarely been reported to occur in combination with a component of adenocarcinoma {1200, 1389}. Nasopharyngeal carcinoma may present initially with cervical lymph node metastases. The lymph nodes can be involved extensively or subtly (such as submergence of the tumour in the lymphocyte-rich paracortex). The tumour takes the form of islands and strands, being intermingled with variable numbers of lymphocytes, plasma cells and eosinophils. Some tumour cells can resemble ReedSternberg cells or lacunar cells. Coupled with a dense lymphoid infiltrate, a misdi-agnosis of Hodgkin or non-Hodgkin lym phoma is sometimes made {330,1470}. A desmoplastic stroma may be present. In approximately one fifth of cases, there are epithelioid granulomas, and in half of these cases, the granulomas show caseous necrosis {1470}.

Nasopharyngeal carcinoma may also metastasize as a wholly or partly cystic lesion containing necrotic material.


Practically all tumour cells show strong staining for pan-cytokeratin (AE1/AE3, MNF-116); this uniform staining contrasts with the usually focal staining observed in undifferentiated carcinomas of other sites, such as the lung and thyroid. The staining for high molecular weight cytok-eratins (such as cytokeratin 5/6, 34BE12) is strong, and staining for low molecular weight cytokeratins (such as CAM5.2) is often weaker and sometimes patchy. Cytokeratins 7 and 20 are both negative {801}. In undifferentiated nonkeratinizing carcinoma, the cytokeratin immunostain highlights the scanty wisps of cytoplasm that wrap around the large nucleus and extend outward as short narrow processes. As a result of the cell nests being broken up by infiltrating lymphocytes, a distinctive reticulated or meshwork pattern is produced. In differentiated nonkera-tinizing carcinoma, the tumour cells, with a broader rim of cytoplasm, are obviously polygonal on immunostaining for cytokeratin.

Immunoreactivity for epithelial membrane antigen in nasopharyngeal carcinoma is often only focal {816}. In most cases, the tumour exhibits strong nuclear staining for p63, a basal cell marker that normally highlights the basal and parabasal cells of the overlying stratified squamous epithelium. The lymphoid cells represent a mixture of T cells and B cells, usually with the former predominating, especially within and around the tumour islands {854,883, 1070,1962,2912}. At least a proportion of the T cells are activated cytotoxic cells. The plasma cells are polyclonal. There are variable numbers of scattered S100

Fig. 2.12 Nasopharyngeal nonkeratinizing carcinoma, undifferentiated subtype. A In-situ hybridization for EBER shows that all tumour cells exhibit nuclear labeling. B Immunostaining for pan-cytokeratin highlights the surface epithelium as well and irregular clusters and sheets of positive cells (carcinoma) in the stroma. C Immunostaining for cytokeratin usually reveals a meshwork pattern of staining.

Fig. 2.12 Nasopharyngeal nonkeratinizing carcinoma, undifferentiated subtype. A In-situ hybridization for EBER shows that all tumour cells exhibit nuclear labeling. B Immunostaining for pan-cytokeratin highlights the surface epithelium as well and irregular clusters and sheets of positive cells (carcinoma) in the stroma. C Immunostaining for cytokeratin usually reveals a meshwork pattern of staining.

Fig. 2.13 Metastatic nasopharyngeal carcinoma in lymph node. A Fine needle aspiration smear shows tight clusters of tumour cells among small lymphocytes. B In histological sections, examination under medium magnification often reveals areas where cohesive tumour growth is evident. C The epithelial nature of the tumour is readily confirmed by immunostaining for cytokeratin, whereby a meshwork pattern of staining is often observed.

protein-positive dendritic cells. Some studies have reported the following features to be associated with a better prognosis: high density of dendritic cells; high number of infiltrating lymphocytes; and low number of granzyme B-positive cyto-toxic cells {854,883,1903,1962,2912}.

Epstein-Barr virus detection

Nonkeratinizing nasopharyngeal carcinoma is associated with Epstein-Barr virus (EBV) in practically 100% of cases, irrespective of the ethnic background of the patient. EBV latent membrane pro-tein-1 (LMP1) is usually positive in only 30-40% of cases, and the immunostain-ing is often patchy and weak, and thus is not a reliable method to demonstrate the presence of EBV {16,961,1988,2061}. The simplest and most reliable way to demonstrate EBV is in-situ hybridization for EBV encoded early RNA (EBER), which is present in abundance in cells latently infected by EBV. Practically all the tumour cells should show nuclear labelling {1137,1157,1176,2061,2233, 2638,2684}. In-situ hybridization for EBER can aid in the diagnosis of nasopharyngeal carcinoma if there are difficulties in distinguishing between carcinoma and reactive epithelial atypia. A positive result also strongly suggests a nasopharyngeal origin (although not entirely specific) for a metastatic nonker-atinizing carcinoma of unknown primary. On the other hand, it is less reliable to use polymerase chain reaction to look for EBV in the tumour, because even a few bystander EBV-positive lymphocytes can give rise to a positive result {2638}.


Nasopharyngeal aspirate or brush is used in some centres to produce cyto-logic preparations for diagnosis of nasopharyngeal carcinoma. However, since the diagnostic sensitivity of nasopharyngeal cytology is limited (7090%) {387,1001}, nasopharyngeal biopsy is the preferred method for obtaining a definitive histological diagnosis {387}. On the other hand, fine needle aspiration cytological examination of enlarged cervical lymph nodes is invaluable in reaching a diagnosis of metastatic nasopha-ryngeal carcinoma, either for initial diagnosis or staging {380,1355}. The aspirate smears show, in a background of lymphocytes and plasma cells, irregular clusters of large cells with overlapping vesicular nuclei and large nucleoli. The cytoplasm of these cells is often fragile and barely visible. There are commonly many naked nuclei {1760}. The presence of dispersed large tumour cells among the lymphoid cells may result in a pattern strongly reminiscent of Hodgkin lymphoma {1355}. The diagnosis can be readily confirmed by immunostaining for cytokeratin and in-situ hybridization for EBER either on the cell smears or cell block preparations.

Electron microscopy.

Although squamous differentiation is primitive or not evident in most cases of nasopharyngeal carcinoma at the light microscopic level, there is usually convincing evidence of squamous differentiation at the ultrastructural level. At least some carcinoma cells contain small bundles of tonofilaments or tonofibrils, in addition to well-formed desmosomes {1470, 1513,2082,2568}.

Differential diagnosis

Crush artefacts are common in nasopha-ryngeal biopsies, making it difficult to determine whether the observed distorted cells represent carcinoma or merely lymphoid cells. Such biopsies should be scrutinized in the better-preserved areas for tumour cell clusters. If there are uncertainties, immunostaining for cytok-eratin is of great help in reaching a diagnosis of nasopharyngeal carcinoma. In the non-neoplastic nasopharyngeal mucosa, cytokeratin immunostaining highlights the sharply delineated surface and crypt epithelium, with no positive cells in the stroma other than those in seromucinous glands. Mucosa involved by nasopharyngeal carcinoma typically shows irregular clusters of cytokeratin-positive cells in the stroma.

Fig. 2.14 Nasopharyngeal mucosa. A Germinal centre cells mimicking nasopharyngeal carcinoma. B Nasopharyngeal lymphoid hyperplasia mimicking nasopharyngeal carcinoma. In the left field, the venule with no obvious lumen can also be mistaken for a cluster of carcinoma cells.

Fig. 2.15 Nasopharyngeal keratinizing squamous cell carcinoma, well differentiated. A The tumour shows invasion into the stroma. B Irregular islands of carcinoma infiltrate an abundant desmoplastic stroma. The tumour cells show obvious squamous differentiation and keratinization.

A number of benign cellular changes can mimic nonkeratinizing carcinoma. (1) Clusters of germinal centre cells may be mistaken for carcinoma because of the presence of large cells with vesicular nuclei and the absence of a well-defined mantle zone. The identification of admixed centrocytes (smaller "atypical" cells with irregular-shaped or angulated nuclei) and tingible-body macrophages points toward the lymphoid nature of the large cells, which can be confirmed by immunostaining (leucocyte common antigen positive, cytokeratin negative) {2317}. (2) A tangentially sectioned crypt harbouring cells with reactive changes that include nuclear enlargement can produce a pattern simulating an island of carcinoma lying in a lymphoid cell-rich stroma. In contrast to nasopharyngeal carcinoma, the nuclei are not as large and thus not so crowded, and the nucle-oli are not as prominent. A negative in-situ hybridization for EBER would render a diagnosis of nasopharyngeal carcinoma most unlikely {2318}. (3) The nasopharyngeal mucosa can sometimes exhibit reactive lymphoid hyperplasia, accompanied by an increased number of immunoblasts in the lymphoid stroma, raising a suspicion for carcinoma. In contrast to the latter, the large cells are non-cohesive and have well-defined amphophilic cytoplasm. The diagnosis can be confirmed by a lack of cytokeratin immunoreactivity as well as positive immunostaining for lymphoid markers in the large cells {323}. (4) The lymphoid tissue-associated venules lined by plump endothelial cells with vesicular nuclei may be mistaken for clusters of carcinoma cells. The presence of distinct basement membrane around the groups of cells, lack of large nucleoli, and negative staining for cytokeratin would be against the diagnosis of carcinoma. Distinction between nonkeratinizing carcinoma and large cell lymphoma can at times be difficult. In the nasopharyngeal mucosa or metastatic deposit in lymph node, dispersed growth of the carcinoma cells and accompanying eosinophil infiltration may lead to a misdiagnosis of Hodgkin lymphoma {330,394,2880}. Features favouring a diagnosis of carcinoma include the presence of cohesive cell groups in some foci (best appreciated at medium magnification) and the generally poorly defined cell borders; the diagnosis can be readily confirmed by immunostaining for cytokeratin. Nasopharyngeal carcinoma with marked cellular spindling can mimic a highgrade sarcoma. In most cases, the diagnosis can be reached by identifying in some foci a component of typical nasopharyngeal carcinoma, and can be further confirmed by cytokeratin immunoreactivity.

Post-treatment biopsies

After treatment by radiation therapy, it may take weeks (up to 10 weeks) for the nasopharyngeal carcinoma to disappear histologically {1401}. The radiated carcinoma cells usually show evidence of radiation injury in the form of enlarged and bizarre nuclei, accompanied by an increased amount of cytoplasm that is often finely vacuolated. If biopsy is positive, repeat biopsies should be taken every two weeks - remission is defined by two subsequent negative biopsies {1401,1402,1886}.

Radiation-induced changes in the normal nasopharyngeal mucosa can be mistaken for malignancy. The surface or crypt epithelium can exhibit enlarged, hyperchromatic or even bizarre nuclei, but such changes can be recognized to be benign because they are limited to some but not all cells (random cytologic atypia) and the normal nuclear-cytoplas-mic ratio is maintained. Mucosal epithelial atypia usually does not persist beyond one year. If there are uncertainties as to whether the atypical cells represent residual carcinoma or irradiated normal cells, positive in-situ hybridization for EBER would strongly favour the former interpretation. There can also be bizarre stromal cells (radiation fibrob-lasts) with large smudged nuclei or large vesicular nuclei with prominent nucleoli; these atypical cells can persist for many years. These cells can be distinguished from residual or recurrent carcinoma by their occurrence as single cells and by the amphophilia of the cytoplasm. The stroma frequently contains ectatic blood vessels showing variable degrees of radiation injury such as enlarged prominent endothelial cells and abundant fibrinoid deposits.

Some patients with nasopharyngeal carcinoma develop local recurrence. The nasopharyngeal biopsies should be interpreted in the same way as for patients without a prior history of nasopharyngeal carcinoma. The recurrence can be morphologically identical to the original tumour, or may show a slightly greater degree of squamous dif

Infiltrative Ductal Carcinoma
Fig. 2.16 Basaloid squamous cell carcinoma of the nasopharynx. The basaloid tumour cells show a festooning growth pattern, and are interspersed by tumour cells with squamous differentiation.

ferentiation. Some recurrences, especially those occurring after a long interval (>5 years), may represent new primaries rather than a genuine relapse of the original tumours {1445}. Radiation-induced tumours in the nasopharynx typically develop after a long latency period, and usually take the form of keratinizing squamous cell carcinomas or sarcomas (especially osteosarcomas) {403,600}.

Keratinizing squamous cell carcinoma


This is an invasive carcinoma showing obvious squamous differentiation at the light microscopic level, in the form of intercellular bridges and/or keratinization over most of the tumour, morphologically similar to keratinizing squamous cell carcinomas occurring in other head and neck mucosal sites {2317}. The degree of differentiation can be further graded as: well differentiated (most common), moderately differentiated and poorly differentiated. The tumour typically grows in the form of irregular islands, accompanied by an abundant desmoplastic stroma infiltrated by variable numbers of lymphocytes, plasma cells, neutrophils and eosinophils {1555}. The tumour cells are polygonal and stratified. The cell borders are distinct and separated by intercellular bridges. The cells in the centres of the islands or facing the surface often show a greater amount of eosinophilic glassy cytoplasm, sometimes with identifiable cytoplasmic tonofibrils, indicative of cellular keratinization. Occasionally keratin pearls are formed {2735}. The nuclei often show hyperchromasia, and the degree of nuclear pleomorphism ranges from mild to marked. The surface epithelium is frequently involved, apparently representing carcinoma in-situ. Keratinizing squamous cell carcinoma can arise de novo or as a radiation-associated carcinoma occurring many years after radiation therapy for nonkeratinizing nasopharyngeal carcinoma {403,2316, 2735}. Compared with nonkeratinizing carcinoma, keratinizing squamous cell carcinoma shows a greater propensity for locally advanced tumour growth (76% versus 55%) {2136} and a lower propensity for lymph node metastasis (29% versus 70%) {1859}. While some studies suggest that this subtype of nasopharyn-geal carcinoma has lower responsiveness to radiation therapy and a worse prognosis compared with nonkeratiniz ing carcinoma {1122,1859,2136,2318}, others have not found this subtype to differ in biological behaviour {363,778}.

Immunoprofile and Epstein-Barr virus detection

Keratinizing squamous cell carcinoma shows immunoreactivity for pan-cytoker-atin, high molecular-weight cytokeratin, and focally epithelial membrane antigen. For radiation-induced keratinizing squa-mous cell carcinoma, there is no association with EBV {403}. However, for de novo keratinizing squamous cell carcinomas, data on the EBV status are conflicting. In general, the patients have lower or negative IgA titres against EBV compared with nonkeratinizing carcinomas {1486,1860,2549}. Molecular studies of EBV in the tumour tissues have yielded conflicting results. Summarizing the literature, it appears that EBV is almost always positive in areas endemic for nasopharyngeal carcinoma, EBV is often positive in intermediate incidence areas, while EBV is positive in only a proportion of cases in low incidence areas {405, 580,599,961,1124,1125,1157,1176,1262 ,1885,1892,1988,2894}. Keratinizing squamous cell carcinomas tend to carry lower copy numbers of EBV compared with nonkeratinizing carcinomas {2108}. On in situ hybridization, the nuclear signals of EBER are usually confined to the less differentiated cells (basal cells that surround the individual tumour islands), but not in the cells showing obvious squamous differentiation. The role of human papillomavirus in ker-atinizing squamous cell carcinoma remains uncertain {1125}.

Differential diagnosis

The frank invasive growth, nuclear atypia and obvious squamous differentiation usually permit a straight-forward diagnosis of keratinizing squamous cell carcinoma to be made. However, in some cases, particularly those arising after radiation therapy for nonkeratinizing nasopharyngeal carcinoma, distinction between a very well differentiated keratinizing squa-mous cell carcinoma and squamous metaplasia/hyperplasia can be extremely difficult, since the nuclear atypia can be very subtle and focal, and invasion may not be obvious in the former. Assessment of invasion is further hampered by the abundant fibrinous deposits in the stro-ma related to prior radiation, and the usual desmoplastic stroma may be lacking. To arrive at a definitive diagnosis, sometimes multiple biopsies are required to identify convincing stromal invasion as well as focal mild nuclear atypia.

Basaloid squamous cell carcinoma

Several cases of basaloid squamous cell carcinoma, morphologically identical to the same tumour more commonly occur

Fig. 2.17 Pure nasopharyngeal carcinoma-in-situ. A The surface epithelium consists of disarrayed cells with enlarged and crowded nuclei which vary in size, compatible with carcinoma in-situ. This patient was not given any treatment, and has remained disease-free at 7 years. B In-situ hybridization for EBER shows that the atypical epithelial cells are positive. C In this unusual example, the cells that comprise the surface epithelium exhibit marked nuclear pleomorphism and hyper-chromasia. This example of radiation-associated carcinoma-in-situ has subsequently evolved into an invasive keratinizing squamous cell carcinoma.

ring in other head and neck sites (See chapter on hypophyarnx, larynx and trachea for details), have been reported to occur as primary tumours of the nasopharynx {116,117,1790,1997,2714}. Among the 6 cases with information, the M:F ratio is 2:1, and patients' ages ranged from 27-79 years (mean 55 years). Four cases had stage T3 or T4 disease; and two had lymph node metastasis. None had distant metastasis at presentation. On follow-up, three patients had no evidence of disease at 34-52 months; three were alive with disease at 19-46 months. The tumour appears to show a lower clinical aggressiveness compared with basaloid squamous cell carcinoma occurring in other head and neck sites. Among 4 cases tested for EBV, all three Asian cases were positive, while one Caucasian case were negative {1790,2714}.

Precursor lesions

In biopsies of nasopharyngeal carcino ma, an in-situ or intraepithelial component is identified in only 3-8% of cases, but it is often difficult to determine whether the invasive carcinoma has originated from the overlying in situ carcinoma or has merely invaded the surface epithelium {364,1504,1989,2852,2911}. Pure nasopharyngeal carcinoma in-situ, as confirmed by multiple biopsies to rule out an invasive component, is very rare {419,1989,2911}. These findings suggest that most nasopharyngeal carcinomas do not originate from nasopharyngeal carcinoma in-situ, or the evolution from the latter to the former occurs over a short time scale such that the latter is rarely detected.

Histologically, pure nasopharyngeal car-cinoma-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. Sometimes there can be scattered amyloid globules. Some attempts have been made to grade the spectrum of intraepithelial neo-plastic changes (dysplasia/carcinoma-in situ, or nasopharyngeal intraepithelial neoplasia) in the nasopharynx, but repro-ducibility and difficulties in recognizing the lower grade lesions remain an issue. 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 {419,1971,2813}. Analysis of the EBV termini shows the virus to be in a clonal form, providing indirect support for the clonality of the epithelial proliferation {1989}. Thus in situ hybridization for EBER may aid in the distinction between carcinoma-in-situ and non-specific reactive atypia of the nasopharyngeal epithelium.

There are only limited data on the natural history of untreated pure nasopharyn-geal carcinoma in-situ (or dysplasia). A proportion of patients develop invasive cancer on follow-up {1971,1989}.


Nasopharyngeal carcinoma arises from the surface or crypt epithelium of the nasopharyngeal mucosa. In some cases, the tumour appears to arise from the basal layers of the stratified squamous epithelium, a finding further supported by the strong immunoreactivity for p63 in both the tumour and normal basal cells.

Somatic genetics

Nasopharyngeal carcinoma (NPC) is believed to result from accumulation of multiple genetic alterations and Epstein-Barr virus (EBV) latent infection in the

Fig. 2.18 Nasopharyngeal carcinoma with an intraepithelial component.The invasive carcinoma is accompanied by an abnormal surface epithelium comprising similar cells.

nasopharyngeal epithelial cells {611, 1542}. EBV genome is detected in all undifferentiated NPC cells and in highgrade dysplastic lesions of the nasopharynx, but rarely found in the adjacent normal nasopharyngeal epithelial cells or in the low-grade dysplastic lesions {361,1989}. The expression of EBV latent genes (e.g. EBNA1, LMP-1, LMP-2) may alter multiple signal transduction pathways and thus contribute to the transformation of the nasopharyngeal epithelium {611}.

Cytogenetics and comparative genomic hybridization (CGH)

Only few well-characterised karyotypes of NPC have been described. Despite the many complex rearrangements found, rearrangement and deletion on chromosome 3 have been consistently noted in this cancer {1141,2707,2813}. The spectral karyotyping (SKY) analyses have defined the common chromosomal regions of loss including 3p12-p21, 11 q 14-qter as well as the common regions of gain including 7p15-p14, 7q11.2-q21, 8q21.1-q22, 12q22-q24.1 and 20q were frequently detected {2813}. CGH studies have identified multiple recurrent chromosomal aberrations including loss on chromosomes 3p, 9p, 9q, 11q, 13q, 14q and 16q and gains of 1q, 3q, 12p, and 12q. Common regions of loss are 3p14-21, 14q24-qter, 11q21-qter while common regions of gains are 3q21-26 and 12q13-15 {413,716,1148}. Array-based CGH analyses and fluorescence in-situ hybridization (FISH) analyses have identified a cryptic amplification at 3q26 {964,1149}.

Molecular genetic alterations

In concordance with CGH results, loss of heterozygosity (LOH) studies have revealed high frequencies of deletion on chromosomes 3p, 9p, 9q, 11q, 13q, 14q and 16q. Multiple minimally deleted regions are identified at 3p14-24.2, 11 q21-23, 13q 12—14, 13q31-32, 14q24-32, and 16q22-23 {1545}. The characteristic LOH on 3p, 9p, and 14q in almost all tumours suggests that the putative tumour suppressor genes located in these regions probably play important roles in the genesis of NPC. Moreover, deletions on 3p and 9p have been shown to be early events in NPC tumorigenesis {360,361}. Inactivation of the P16 tumour suppressor gene on 9p21 by homozygous dele tion and methylation has been shown to be the most common molecular alteration in NPC tumourigenesis {1541, 1543}. Loss of P16 may result in cell cycle deregulation, while aberrations of the two major cell cycle regulators, P53 and RB, are rare {2453,2504}. Some studies have also found a high frequency of promoter hypermethylation of RASSF1A, a tumour suppressor gene on 3p21.3, in 70-80% of all cases of primary tumours {1403,1544}. The tumour suppressor function of RASSF1A may involve the DNA repair system and the RAS-dependent growth control. Other NPC-associated genes in the minimally deleted regions include TSLC1 at 11q23, EDNRB at 13q22, E-CADHERIN and RB2/130 at 16q {457,1542,1546,2642}. Epigenetic inactivation of multiple cancer-associated genes is common in NPC. Aside from P16 and RASSF1A, high frequencies of aberrant methylation are detected in EDNRB (90.5%), RARB2 (80%), DAP-kinase (76%), RIZ1 (60%) and E-CADHERIN (52%) {390,1403, 1546}. Widespread hypermethylation of CpG islands over the genome imply a "methylator" phenotype in this cancer.

Expression profiles / Proteomics

In NPC, P53 mutation is rare, but DN-P63, a P53 homologue, is consistently over-expressed and may block P53-mediated transactivation and apoptotic network in cancer cells {506,2453}. Frequent aberrant expression of the cyclin D1, P27 and BCL-2 may also be involved in dysregulation of cell proliferation and apoptosis pathway {100,1415, 1566}. Overexpression of the hypoxia associated proteins, HIF-alpha, CA IX, and VEGF, is common and associated with poor prognosis {1150}. High MET protein expression level correlates with poor survival in late-stage NPC {2094}.

Genetic susceptibility

There is strong evidence that genetic predisposition is involved in the genesis of NPC. Epidemiological studies strongly support the existence of susceptible populations in the world: the prevalence of NPC is highly variable in different ethnic groups {1979}; migrants from high-risk areas continue to exhibit high risk of NPC {952,1501}, familial clustering of NPC is frequently observed {2893}.

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