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Nasopharyngeal Carcinoma

Synonyms: Lymphoepithelioma-Like Carcinoma, Lymphoepithelioma, Regaud's-Type Lymphoepithelioma, Schmincke-Type Lymphoepithelioma

Undifferentiated nasopharyngeal adenocarcinoma composed of cells growing in a diffuse syncytial pattern (Schmincke type).

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Definition

Malignant epithelial tumor arising in the nasopharyngeal mucosa, that includes keratinizing squamous cell carcinoma and nonkeratinizing squamous cell carcinoma (differentiated and undifferentiated).

Clinical Features

Leading cause of death in Southeast Asia:
- less common cause in northern Africa1–3
Age–incidence curve bimodal:
- peaks 15–25 years and 60–69 years 4–6
Sometimes familial aggregation 7

Spread and Metastases

Unilateral cervical lymphadenopathy most common presentation
Great propensity to metastasize to regional nodes
Metastases may also develop in distant sites, such as skeletal system8,9
If arising from fossa of Rosenmuller:
- frequently extends to paranasopharyngeal space, from which it can grow along perineurial space of the trigeminal nerve 10

Pathogenesis

Evidence strongly suggests combined action of:
- genetic predisposition
- environmental factors
- Epstein–Barr virus (EBV):11–15
  - within tumor EBV DNA is homogeneous and clonal with regard to repeat sequences 16
  - expression of specific viral messenger RNAs or gene products consistently detected within all tumor cells17,18
  - EBV in tumor tissue 19–25 (Fig. 1
    Fig. 1: Immunohistochemical demonstration of EBER in nasopharyngeal undifferentiated carcinoma.
    )
Proposed that:
- tumor initiation requires EBV expression
- induction of preneoplastic events and maintenance of tumor-cell phenotype require critical cellular genes26

Gross Pathology

May be difficult to detect
Random blind biopsies from nasopharyngeal area should be taken whenever diagnosis is suspected, particularly from fossa of Rosenmüller27

Histopathology

Crucial distinction is between:
- (keratinizing) squamous cell carcinomas:
  - show clearcut evidence of keratinization
  - less marked association with EBV
  - older age group28,29
- nonkeratinizing carcinomas:
  - do not show clearcut evidence of keratinization 30
  - subdivided into:
    - differentiated:
      - stratified or tiled arrangement
      - well-defined cell margins
    - undifferentiated31,32
      syncytial appearance
      indistinct cell margins
      some tumor cells may be spindle-shaped
  - high proportion, particularly if undifferentiated, accompanied by prominent inflammatory infiltrate:
    - may be other inflammatory cells such as:
      - eosinophils 33
      - rarely, epithelioid and multinucleated giant cells
Two patterns of growth, sometimes in combination:
- Regaud's-type:
  - inaccurate designation
  - well-defined aggregates of epithelial cells surrounded by fibrous tissue and lymphoid cells
- Schmincke-type:
  - inaccurate designation
  - neoplastic epithelial cells:
    - grow diffusely (Fig. 2
      Fig. 2: Undifferentiated nasopharyngeal adenocarcinoma composed of cells growing in a diffuse syncytial pattern (Schmincke type).
      )
    - closely intermingled with inflammatory cells
    - nuclei tend to be:
      - vesicular
      - smooth outline
      - nucleolus:
        single
        large
        sharply etched
        eosinophilic34
Occasionally oval or spindle shaped tumor cells (Fig. 3
Fig. 3: Undifferentiated nasopharyngeal carcinoma composed of oval and spindle tumor cells.
)
In situ carcinoma in a minority of cases35
Rarely:
- entirely in situ carcinoma36
- amyloid deposition in tumor stroma37
Rare microscopic forms:
- basaloid squamous cell carcinoma38
- papillary adenocarcinoma:39
  - gland forming
  - papillary
  - mucin producing
  - immunoreactive for keratin and CEA
  - excellent prognosis39
Ultrastructurally:
- tonofilaments and complex desmosomes in tumor cells:40
  - suggest origin from basal layers of pseudostratified and stratified epithelia41

Nodal Metastases

May:
- simulate large cell lymphoma42
- be marked infiltration by eosinophils:
  - may result in misdiagnosis of Hodgkin's lymphoma43,44
- be granulomatous reaction with varying degrees of necrosis 45 (Figs 4 and 5
  Fig. 4: Undifferentiated nasopharyngeal carcinoma metastatic to cervical lymph node associated with granuloma formation.
  Fig. 5: Undifferentiated nasopharyngeal carcinoma metastatic to cervical lymph node associated with xanthogranulomatous reaction.
  )
- be marked cystic changes, simulating benign branchial cleft cyst (Figs 6 and 7
  Fig. 6: Cystic metastasis of nasopharyngeal lymphoepithelioma to cervical lymph node simulating the pattern of growth of branchial cleft cyst.
  Fig. 7: Cystic metastasis of nasopharyngeal lymphoepithelioma to cervical lymph node simulating the pattern of growth of branchial cleft cyst.
  )

Special Stains and Immunohistochemistry

Reactivity for:
- keratin (always):
  - most reliable marker for identification
- epithelial membrane antigen (usually)
- CEA (occasionally)46–49
May be population of S-100 protein-positive dendritic cells 50

Diagnosis

In United States support for presumptive diagnosis provided by consistent detection of:
- IgG antibodies:
  - against early EBV antigen
  - 30% false-positives
- IgA antibodies:
  - against capsid viral antigen51–54
  - 9–18% false-positives

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Nasopharyngeal Carcinoma

Large cell malignant lymphoma:
- may be confused with Schmincke-type undifferentiated carcinoma
- nuclei of malignant lymphoma usually:
  - more irregularly shaped
  - coarser chromatin
  - nucleoli smaller and either basophilic or amphophilic
- Nodal metastases may be confused with:
  - large cell lymphoma:42
    - useful features in metastatic carcinoma are:
      - focal (predominantly sinusal) nature of involvement
      - large vesicular nuclei with single prominent nucleolus
- Hodgkin's lymphoma:
  - when there is a marked infiltration by eosinophils43,44
- benign branchial cleft cyst:
  - when marked cystic changes (see Figs 6 and 7 )

Staging/Grading

Several staging systems proposed
System devised by Ho best predictor of prognosis 55

Genetics

Often:
- overexpression of p53 product:
  - correlates with presence of EBV infection56,57
- lack p16/MTS1 tumor suppressor protein
- overrepresentation of c-myc and Int-2 58,59
Consistently express Rb gene product

Management

Radiation therapy:
- failure-free survival 34%60
- some suggest combining it with chemotherapy61,62

Prognosis

Significantly affected by:
- clinical staging 63,64
- location of regional metastases:
  - better for:
    - metastases limited to upper neck as opposed to lower cervical regions 65
  - cranial nerve, orbit, and intracranial involvement confer particularly unfavorable prognosis63
Worse for keratinizing squamous cell carcinoma than for others,66,67 and for latter claimed that prognosis is worse if one or more of:
- marked anaplasia and/or pleomorphism 68
- high cell proliferation rate:
  - measured with mitotic count or proliferation-related immunomarkers69
- lack of lymphocytic infiltrate67
- high density S-100 protein-positive dendritic cells68,70
- high microvessel count 71
- presence of c-erb B-2 expression71

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Last updated: 4 Mar 2006